Most RNA polymerases can initiate transcription from diverse DNA template sequences with relatively few outright sequence restraints. Recent reports have demonstrated that failure to subdue the promiscuity of RNA polymerase in vivo can severely impede cell function. This phenomenon appears common to all cell types with undesirable effects ranging from growth inhibition in prokaryotes to cancer in higher organisms. Here we discuss similarities and differences in strategies employed by cells to minimise spurious transcription across life's domains.