The eukaryotic origin recognition complex (ORC) not only selects the sites where prereplication complexes are assembled and DNA replication begins, it is the first in a series of multiple coherent pathways that determines when prereplication complexes are assembled. Data from yeast, frogs, flies and mammals present a compelling case that one or more of the six ORC subunits undergoes cell cycle dependent modifications involving phosphorylation and ubiquitination that repress ORC activity during S, G2 and M-phases. ORC activity is not restored until mitosis is complete and a nuclear membrane is present. In yeast, frogs and mammals, the same cyclin-dependent protein kinase [Cdk1(Cdc2)] that initiates mitosis also inhibits assembly of functional ORC/chromatin sites. In yeast, ORC remains bound to chromatin throughout cell division, but in the metazoa either ORC or the Orc1 subunit appears to cycle on and off the chromatin. Thus, this "ORC cycle" is the premier step in preventing rereplication of DNA during a single cell division cycle.