diff --git a/src/toil/common.py b/src/toil/common.py
index d0eb1bc8..d4a8c73c 100644
--- a/src/toil/common.py
+++ b/src/toil/common.py
@@ -198,7 +198,7 @@ class Config:
         self.writeLogs = None
         self.writeLogsGzip = None
         self.writeLogsFromAllJobs: bool = False
-        self.write_messages: str = ""
+        self.write_messages: Optional[str] = None
 
         # Misc
         self.environment: Dict[str, str] = {}
@@ -222,6 +222,24 @@ class Config:
         # CWL
         self.cwl: bool = False
 
+    def prepare_start(self) -> None:
+        """
+        After options are set, prepare for initial start of workflow.
+        """
+        self.workflowAttemptNumber = 0
+
+    def prepare_restart(self) -> None:
+        """
+        Before restart options are set, prepare for a restart of a workflow.
+        Set up any execution-specific parameters and clear out any stale ones.
+        """
+        self.workflowAttemptNumber += 1
+        # We should clear the stored message bus path, because it may have been
+        # auto-generated and point to a temp directory that could no longer
+        # exist and that can't safely be re-made.
+        self.write_messages = None
+        
+
     def setOptions(self, options: Namespace) -> None:
         """Creates a config object from the options object."""
         OptionType = TypeVar("OptionType")
@@ -407,6 +425,8 @@ class Config:
         set_option("write_messages", os.path.abspath)
 
         if not self.write_messages:
+            # The user hasn't specified a place for the message bus so we
+            # should make one.
             self.write_messages = gen_message_bus_path()
 
         assert not (self.writeLogs and self.writeLogsGzip), \
@@ -947,14 +967,14 @@ class Toil(ContextManager["Toil"]):
             self.options.caching = config.caching
 
         if not config.restart:
-            config.workflowAttemptNumber = 0
+            config.prepare_start()
             jobStore.initialize(config)
         else:
             jobStore.resume()
             # Merge configuration from job store with command line options
             config = jobStore.config
+            config.prepare_restart()
             config.setOptions(self.options)
-            config.workflowAttemptNumber += 1
             jobStore.write_config()
         self.config = config
         self._jobStore = jobStore
diff --git a/src/toil/lib/aws/session.py b/src/toil/lib/aws/session.py
index 4ef36f16..cbc2b686 100644
--- a/src/toil/lib/aws/session.py
+++ b/src/toil/lib/aws/session.py
@@ -18,7 +18,6 @@ import os
 import re
 import socket
 import threading
-from functools import lru_cache
 from typing import (Any,
                     Callable,
                     Dict,
@@ -37,16 +36,33 @@ import boto3.resources.base
 import boto.connection
 import botocore
 from boto3 import Session
+from botocore.client import Config
 from botocore.credentials import JSONFileCache
 from botocore.session import get_session
 
 logger = logging.getLogger(__name__)
 
-@lru_cache(maxsize=None)
-def establish_boto3_session(region_name: Optional[str] = None) -> Session:
+# A note on thread safety:
+#
+# Boto3 Session: Not thread safe, 1 per thread is required.
+#
+# Boto3 Resources: Not thread safe, one per thread is required.
+#
+# Boto3 Client: Thread safe after initialization, but initialization is *not*
+# thread safe and only one can be being made at a time. They also are
+# restricted to a single Python *process*.
+#
+# See: <https://stackoverflow.com/questions/52820971/is-boto3-client-thread-safe>
+
+# We use this lock to control initialization so only one thread can be
+# initializing Boto3 (or Boto2) things at a time.
+_init_lock = threading.RLock()
+
+def _new_boto3_session(region_name: Optional[str] = None) -> Session:
     """
-    This is the One True Place where Boto3 sessions should be established, and
-    prepares them with the necessary credential caching.
+    This is the One True Place where new Boto3 sessions should be made, and
+    prepares them with the necessary credential caching. Does *not* cache
+    sessions, because each thread needs its own caching.
 
     :param region_name: If given, the session will be associated with the given AWS region.
     """
@@ -55,35 +71,12 @@ def establish_boto3_session(region_name: Optional[str] = None) -> Session:
     # See https://github.com/boto/botocore/pull/1338/
     # And https://github.com/boto/botocore/commit/2dae76f52ae63db3304b5933730ea5efaaaf2bfc
 
-    botocore_session = get_session()
-    botocore_session.get_component('credential_provider').get_provider(
-        'assume-role').cache = JSONFileCache()
-
-    return Session(botocore_session=botocore_session, region_name=region_name, profile_name=os.environ.get("TOIL_AWS_PROFILE", None))
-
-@lru_cache(maxsize=None)
-def client(service_name: str, *args: List[Any], region_name: Optional[str] = None, **kwargs: Dict[str, Any]) -> botocore.client.BaseClient:
-    """
-    Get a Boto 3 client for a particular AWS service.
-
-    Global alternative to AWSConnectionManager.
-    """
-    session = establish_boto3_session(region_name=region_name)
-    # MyPy can't understand our argument unpacking. See <https://github.com/vemel/mypy_boto3_builder/issues/121>
-    client: botocore.client.BaseClient = session.client(service_name, *args, **kwargs) # type: ignore
-    return client
-
-@lru_cache(maxsize=None)
-def resource(service_name: str, *args: List[Any], region_name: Optional[str] = None, **kwargs: Dict[str, Any]) -> boto3.resources.base.ServiceResource:
-    """
-    Get a Boto 3 resource for a particular AWS service.
+    with _init_lock:
+        botocore_session = get_session()
+        botocore_session.get_component('credential_provider').get_provider(
+            'assume-role').cache = JSONFileCache()
 
-    Global alternative to AWSConnectionManager.
-    """
-    session = establish_boto3_session(region_name=region_name)
-    # MyPy can't understand our argument unpacking. See <https://github.com/vemel/mypy_boto3_builder/issues/121>
-    resource: boto3.resources.base.ServiceResource = session.resource(service_name, *args, **kwargs) # type: ignore
-    return resource
+        return Session(botocore_session=botocore_session, region_name=region_name, profile_name=os.environ.get("TOIL_AWS_PROFILE", None))
 
 class AWSConnectionManager:
     """
@@ -98,6 +91,10 @@ class AWSConnectionManager:
     connections to multiple regions may need to be managed in the same
     provisioner.
 
+    We also support None for a region, in which case no region will be
+    passed to Boto/Boto3. The caller is responsible for implementing e.g.
+    TOIL_AWS_REGION support.
+
     Since connection objects may not be thread safe (see
     <https://boto3.amazonaws.com/v1/documentation/api/1.14.31/guide/session.html#multithreading-or-multiprocessing-with-sessions>),
     one is created for each thread that calls the relevant lookup method.
@@ -115,18 +112,18 @@ class AWSConnectionManager:
         """
         # This stores Boto3 sessions in .item of a thread-local storage, by
         # region.
-        self.sessions_by_region: Dict[str, threading.local] = collections.defaultdict(threading.local)
+        self.sessions_by_region: Dict[Optional[str], threading.local] = collections.defaultdict(threading.local)
         # This stores Boto3 resources in .item of a thread-local storage, by
-        # (region, service name) tuples
-        self.resource_cache: Dict[Tuple[str, str], threading.local] = collections.defaultdict(threading.local)
+        # (region, service name, endpoint URL) tuples
+        self.resource_cache: Dict[Tuple[Optional[str], str, Optional[str]], threading.local] = collections.defaultdict(threading.local)
         # This stores Boto3 clients in .item of a thread-local storage, by
-        # (region, service name) tuples
-        self.client_cache: Dict[Tuple[str, str], threading.local] = collections.defaultdict(threading.local)
+        # (region, service name, endpoint URL) tuples
+        self.client_cache: Dict[Tuple[Optional[str], str, Optional[str]], threading.local] = collections.defaultdict(threading.local)
         # This stores Boto 2 connections in .item of a thread-local storage, by
         # (region, service name) tuples.
-        self.boto2_cache: Dict[Tuple[str, str], threading.local] = collections.defaultdict(threading.local)
+        self.boto2_cache: Dict[Tuple[Optional[str], str], threading.local] = collections.defaultdict(threading.local)
 
-    def session(self, region: str) -> boto3.session.Session:
+    def session(self, region: Optional[str]) -> boto3.session.Session:
         """
         Get the Boto3 Session to use for the given region.
         """
@@ -134,35 +131,68 @@ class AWSConnectionManager:
         if not hasattr(storage, 'item'):
             # This is the first time this thread wants to talk to this region
             # through this manager
-            storage.item = establish_boto3_session(region_name=region)
+            storage.item = _new_boto3_session(region_name=region)
         return cast(boto3.session.Session, storage.item)
 
-    def resource(self, region: str, service_name: str) -> boto3.resources.base.ServiceResource:
+    def resource(self, region: Optional[str], service_name: str, endpoint_url: Optional[str] = None) -> boto3.resources.base.ServiceResource:
         """
         Get the Boto3 Resource to use with the given service (like 'ec2') in the given region.
+
+        :param endpoint_url: AWS endpoint URL to use for the client. If not
+               specified, a default is used.
         """
-        key = (region, service_name)
+        key = (region, service_name, endpoint_url)
         storage = self.resource_cache[key]
         if not hasattr(storage, 'item'):
-            # The Boto3 stubs are missing an overload for `resource` that takes
-            # a non-literal string. See
-            # <https://github.com/vemel/mypy_boto3_builder/issues/121#issuecomment-1011322636>
-            storage.item = self.session(region).resource(service_name) # type: ignore
+            with _init_lock:
+                # We lock inside the if check; we don't care if the memoization
+                # sometimes results in multiple different copies leaking out.
+                # We lock because we call .resource()
+
+                if endpoint_url is not None:
+                    # The Boto3 stubs are missing an overload for `resource` that takes
+                    # a non-literal string. See
+                    # <https://github.com/vemel/mypy_boto3_builder/issues/121#issuecomment-1011322636>
+                    storage.item = self.session(region).resource(service_name, endpoint_url=endpoint_url) # type: ignore
+                else:
+                    # We might not be able to pass None to Boto3 and have it be the same as no argument.
+                    storage.item = self.session(region).resource(service_name) # type: ignore
+
         return cast(boto3.resources.base.ServiceResource, storage.item)
 
-    def client(self, region: str, service_name: str) -> botocore.client.BaseClient:
+    def client(self, region: Optional[str], service_name: str, endpoint_url: Optional[str] = None, config: Optional[Config] = None) -> botocore.client.BaseClient:
         """
         Get the Boto3 Client to use with the given service (like 'ec2') in the given region.
+
+        :param endpoint_url: AWS endpoint URL to use for the client. If not
+               specified, a default is used.
+        :param config: Custom configuration to use for the client.
         """
-        key = (region, service_name)
+
+        if config is not None:
+            # Don't try and memoize if a custom config is used
+            with _init_lock:
+                if endpoint_url is not None:
+                    return self.session(region).client(service_name, endpoint_url=endpoint_url, config=config) # type: ignore
+                else:
+                    return self.session(region).client(service_name, config=config) # type: ignore
+
+        key = (region, service_name, endpoint_url)
         storage = self.client_cache[key]
         if not hasattr(storage, 'item'):
-            # The Boto3 stubs are probably missing an overload here too. See:
-            # <https://github.com/vemel/mypy_boto3_builder/issues/121#issuecomment-1011322636>
-            storage.item = self.session(region).client(service_name) # type: ignore
+            with _init_lock:
+                # We lock because we call .client()
+
+                if endpoint_url is not None:
+                    # The Boto3 stubs are probably missing an overload here too. See:
+                    # <https://github.com/vemel/mypy_boto3_builder/issues/121#issuecomment-1011322636>
+                    storage.item = self.session(region).client(service_name, endpoint_url=endpoint_url) # type: ignore
+                else:
+                    # We might not be able to pass None to Boto3 and have it be the same as no argument.
+                    storage.item = self.session(region).client(service_name) # type: ignore
         return cast(botocore.client.BaseClient , storage.item)
 
-    def boto2(self, region: str, service_name: str) -> boto.connection.AWSAuthConnection:
+    def boto2(self, region: Optional[str], service_name: str) -> boto.connection.AWSAuthConnection:
         """
         Get the connected boto2 connection for the given region and service.
         """
@@ -172,5 +202,39 @@ class AWSConnectionManager:
         key = (region, service_name)
         storage = self.boto2_cache[key]
         if not hasattr(storage, 'item'):
-            storage.item = getattr(boto, service_name).connect_to_region(region, profile_name=os.environ.get("TOIL_AWS_PROFILE", None))
+            with _init_lock:
+                storage.item = getattr(boto, service_name).connect_to_region(region, profile_name=os.environ.get("TOIL_AWS_PROFILE", None))
         return cast(boto.connection.AWSAuthConnection, storage.item)
+
+# If you don't want your own AWSConnectionManager, we have a global one and some global functions
+_global_manager = AWSConnectionManager()
+
+def establish_boto3_session(region_name: Optional[str] = None) -> Session:
+    """
+    Get a Boto 3 session usable by the current thread.
+
+    This function may not always establish a *new* session; it can be memoized.
+    """
+
+    # Just use a global version of the manager. Note that we change the argument order!
+    return _global_manager.session(region_name)
+
+def client(service_name: str, region_name: Optional[str] = None, endpoint_url: Optional[str] = None, config: Optional[Config] = None) -> botocore.client.BaseClient:
+    """
+    Get a Boto 3 client for a particular AWS service, usable by the current thread.
+
+    Global alternative to AWSConnectionManager.
+    """
+
+    # Just use a global version of the manager. Note that we change the argument order!
+    return _global_manager.client(region_name, service_name, endpoint_url=endpoint_url, config=config)
+
+def resource(service_name: str, region_name: Optional[str] = None, endpoint_url: Optional[str] = None) -> boto3.resources.base.ServiceResource:
+    """
+    Get a Boto 3 resource for a particular AWS service, usable by the current thread.
+
+    Global alternative to AWSConnectionManager.
+    """
+
+    # Just use a global version of the manager. Note that we change the argument order!
+    return _global_manager.resource(region_name, service_name, endpoint_url=endpoint_url)
diff --git a/src/toil/utils/toilStatus.py b/src/toil/utils/toilStatus.py
index a25aa648..45617555 100644
--- a/src/toil/utils/toilStatus.py
+++ b/src/toil/utils/toilStatus.py
@@ -232,11 +232,14 @@ class ToilStatus:
         """
 
         print("\nMessage bus path: ", self.message_bus_path)
-
-        replayed_messages = replay_message_bus(self.message_bus_path)
-        for key in replayed_messages:
-            if replayed_messages[key].exit_code != 0:
-                print(replayed_messages[key])
+        if self.message_bus_path is not None:
+            if os.path.exists(self.message_bus_path):
+                replayed_messages = replay_message_bus(self.message_bus_path)
+                for key in replayed_messages:
+                    if replayed_messages[key].exit_code != 0:
+                        print(replayed_messages[key])
+            else:
+                print("Message bus file is missing!")
 
         return None
 

diff --git a/src/toil/test/src/busTest.py b/src/toil/test/src/busTest.py
index 6be0ab45..da6edb54 100644
--- a/src/toil/test/src/busTest.py
+++ b/src/toil/test/src/busTest.py
@@ -13,12 +13,19 @@
 # limitations under the License.
 
 import logging
+import os
 from threading import Thread, current_thread
+from typing import Optional
 
 from toil.batchSystems.abstractBatchSystem import BatchJobExitReason
 from toil.bus import JobCompletedMessage, JobIssuedMessage, MessageBus, replay_message_bus
+from toil.common import Toil
+from toil.job import Job
+from toil.exceptions import FailedJobsException
 from toil.test import ToilTest, get_temp_file
 
+
+
 logger = logging.getLogger(__name__)
 
 class MessageBusTest(ToilTest):
@@ -95,5 +102,62 @@ class MessageBusTest(ToilTest):
         # And having polled for those, our handler should have run
         self.assertEqual(message_count, 11)
 
+    def test_restart_without_bus_path(self) -> None:
+        """
+        Test the ability to restart a workflow when the message bus path used
+        by the previous attempt is gone.
+        """
+        temp_dir = self._createTempDir(purpose='tempDir')
+        job_store = self._getTestJobStorePath()
+
+        bus_holder_dir = os.path.join(temp_dir, 'bus_holder')
+        os.mkdir(bus_holder_dir)
+
+        start_options = Job.Runner.getDefaultOptions(job_store)
+        start_options.logLevel = 'DEBUG'
+        start_options.retryCount = 0
+        start_options.clean = "never"
+        start_options.write_messages = os.path.abspath(os.path.join(bus_holder_dir, 'messagebus.txt'))
+
+        root = Job.wrapJobFn(failing_job_fn)
+
+        try:
+            with Toil(start_options) as toil:
+                # Run once and observe a failed job
+                toil.start(root)
+        except FailedJobsException:
+            pass
+
+        logger.info('First attempt successfully failed, removing message bus log')
+
+        # Get rid of the bus
+        os.unlink(start_options.write_messages)
+        os.rmdir(bus_holder_dir)
+
+        logger.info('Making second attempt')
+
+        # Set up options without a specific bus path
+        restart_options = Job.Runner.getDefaultOptions(job_store)
+        restart_options.logLevel = 'DEBUG'
+        restart_options.retryCount = 0
+        restart_options.clean = "never"
+        restart_options.restart = True
+
+        try:
+            with Toil(restart_options) as toil:
+                # Run again and observe a failed job (and not a failure to start)
+                toil.restart()
+        except FailedJobsException:
+            pass
+
+        logger.info('Second attempt successfully failed')
+
+
+def failing_job_fn(job: Job) -> None:
+    """
+    This function is guaranteed to fail.
+    """
+    raise RuntimeError('Job attempted to run but failed')
+
 
 

Toil relying on tmpfile directory structure during --restart
This came up here: https://github.com/ComparativeGenomicsToolkit/cactus/issues/987 and, from the stack trace, doesn't look like it's coming from Cactus (?).  

The user reruns with `--restart` and Toil tries to write a temporary file into a temporary directory that doesn't exist.  I'm guessing it was made on the initial run then cleaned since.  But this seems like something that shouldn't happen (ie Toil should only require that the jobstore is preserved not the tempdir).  

I'm not sure if their use of `--stats` which is probably less well tested (at least in Cactus) could be a factor.  


src/toil/test/src/busTest.py::MessageBusTest::test_restart_without_bus_path
src/toil/test/src/busTest.py::MessageBusTest::test_cross_thread_messaging src/toil/test/src/busTest.py::MessageBusTest::test_enum_ints_in_file