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 must cross a point of no return before they replicate their DNA and divide. This commitment decision plays a fundamental role in cancer and degenerative diseases and has been proposed to be mediated by phosphorylation of  (Rb) protein. Here, we show that inactivation of the anaphase-promoting complex/cyclosome (APC^Cdh1) has the necessary characteristics to be the point of no return for cell-cycle entry. Our study shows that APC^Cdh1 inactivation is a rapid, bistable switch initiated shortly before the start of DNA replication by cyclin E/Cdk2 and made irreversible by Emi1. Exposure to stress between Rb phosphorylation and APC^Cdh1 inactivation, but not after APC^Cdh1 inactivation, reverted cells to a mitogen-sensitive quiescent state, from which they can later re-enter the cell cycle. Thus, APC^Cdh1 inactivation is the commitment point when cells lose the ability to return to quiescence and decide to progress through the cell cycle.