The Anaphase-Promoting Complex or Cyclosome (APC/C) is an E3 ubiquitin ligase whose activation requires the binding of a cofactor, either Cdc20 or Cdh1. While APC/C-Cdc20 is a major player during mitotic exit, APC/C-Cdh1 plays a central role in maintaining quiescence and controlling the onset of DNA replication. In addition, APC/C-Cdh1 is essential for endoreduplication, a process in which several rounds of DNA synthesis occur without mitosis. Recent data suggest that the APC/C is also involved in differentiation and metabolism, and plays important roles in postmitotic cells such as neurons. Thus, the APC/C is not only critical for anaphase onset but also regulates many other cellular processes during G1/S or in quiescent cells.