Viruses commonly manipulate cell cycle progression to create cellular conditions that are most beneficial to their replication. To accomplish this feat, viruses often target critical cell cycle regulators in order to have maximal effect with minimal input. One such master regulator is the large, multisubunit E3 ubiquitin ligase anaphase-promoting complex (APC) that targets effector proteins for ubiquitination and proteasome degradation. The APC is essential for cells to progress through anaphase, exit from mitosis, and prevent a premature entry into S phase. These far-reaching effects of the APC on the cell cycle are through its ability to target a number of substrates, including securin, cyclin A, cyclin B, thymidine kinase, geminin, and many others. Recent studies have identified several proteins from a number of viruses that can modulate APC activity by different mechanisms, highlighting the potential of the APC in driving viral replication or pathogenesis. Most notably, human cytomegalovirus (HCMV) protein pUL21a was recently identified to disable the APC via a novel mechanism by targeting APC subunits for degradation, both during virus infection and in isolation. Importantly, HCMV lacking both viral APC regulators is significantly attenuated, demonstrating the impact of the APC on a virus infection. Work in this field will likely lead to novel insights into viral replication and pathogenesis and APC function and identify novel antiviral and anticancer targets. Here we review viral mechanisms to regulate the APC, speculate on their roles during infection, and identify questions to be addressed in future studies.