Polo-like kinase 1 (Plk1) is a key regulator of progression through mitosis. Although Plk1 seems to be dispensable for entry into mitosis, its role in spindle formation and exit from mitosis is crucial. Recent evidence suggests that a major role of Plk1 in exit from mitosis is the regulation of inhibitors of the anaphase-promoting complex/cyclosome (APC/C), such as the early mitotic inhibitor 1 (Emi1) and spindle checkpoint proteins. Thus, Plk1 and the APC/C control mitotic regulators by both phosphorylation and targeted ubiquitylation to ensure the fidelity of chromosome separation at the metaphase to anaphase transition. The mechanisms underlying the control of genomic stability by Plk1 are discussed in this review.