The replicon model devised to explain replication control in bacteria has served as the guiding paradigm in the search for origins of replication in the more complex genomes of eukaryotes. In Saccharomyces cerevisiae, this model has proved to be extremely useful, leading to the identification of specific genetic elements (replicators) and the interacting initiator proteins that activate them. However, replication control in organisms ranging from Schizosaccharomyces pombe to mammals is far more fluid: only a small number of origins seem to represent classic replicators, while the majority correspond to zones of inefficient, closely spaced start sites none of which are indispensable for origin activity. In addition, it is apparent that the epigenetic state of a given sequence largely determines its ability to be used as a replication initiation site. These conclusions were arrived at over a period of three decades, and required the development of several novel replicon mapping techniques, as well as new ways of examining the chromatin architecture of any sequence of interest. Recently, methods have been elaborated for isolating all of the active origins in the genomes of higher eukaryotes en masse. Microarray analyses and more recent high-throughput sequencing technology will allow all the origins to be mapped onto the chromosomes of any organism whose genome has been sequenced. With the advent of whole-genome studies on gene expression and chromatin composition, the field is now positioned to define both the genetic and epigenetic rules that govern origin activity.