The eukaryotic cell cycle comprises an ordered series of events that are controlled by the oscillating activity of cyclin-dependent kinases (Cdks). The unidirectionality of cell cycle transitions is fundamental for successful completion of this cycle. Increasing activity of Cdk1 in complex with its regulatory cyclin, CycB, drives entry into mitosis, whereas subsequent CycB proteolysis promotes exit from mitosis and return of the cell cycle to interphase (Morgan, 2007). It is a commonplace view that the thermodynamically irreversible nature of cyclin proteolysis underlies the unidirectionality of mitotic exit (Lodish et al, 2004). However, in a biological system, steady-state levels of proteins (including CycB) result from the relative rates of protein destruction and de novo synthesis—itself a thermodynamically irreversible reaction. We have, therefore, suggested that proteolysis is insufficient to explain the irreversibility of mitotic exit. Rather, irreversibiltiy requires systems-level feedback that locks the cell cycle machinery in a G1 state, with low Cdk1–CycB activity, after exiting from mitosis (Novak et al, 2007). Proof of principle for this idea has come from experiments in budding yeast (Lopez-Aviles et al, 2009). These show that mitotic exit is driven by cyclin proteolysis but becomes irreversible only when a double-negative feedback loop consisting of the stoichiometric Cdk1 inhibitor, Sic1, is engaged. Here we argue that systems-level feedback is likely to explain the irreversibility of mitotic exit in most, if not all, eukaryotes.