The anaphase promoting complex/cyclosome (APC/C) was initially described as a multi-subunit protein complex that ubiquitinates anaphase inhibitors thus targeting them for destruction by proteasomes to initiate loss of sister chromatid cohesion. However, recent studies have identified important new functions of the APC/C. Moreover, sister centromere separation can occur in the absence of APC/C activity in mammals, indicating that anaphase onset might be triggered by multiple factors. Here we discuss whether the APC/C functions primarily as the anaphase trigger, or whether it has more general properties, relevant for cell cycle control at multiple developmental and cell cycle stages. Additionally, we discuss the validity of the APC-dependent model for sister segregation in mammals.