Mitotic abnormalities are a common feature of human cancer cells, and recent studies have provided evidence that such abnormalities may play a causative, rather than merely incidental role, in tumorigenesis. One such abnormality is prolonged activation of the mitotic checkpoint, which can be provoked by a number of the gene changes that drive tumor formation. At the same time, antimitotic chemotherapeutics exert their clinical efficacy through the large-scale induction of prolonged mitotic checkpoint activation, indicating that mitotic arrest is influential in both the formation and treatment of human cancer. However, how this influence occurs is not well understood. In this perspective, we will discuss the current evidence in support of the potential mechanisms by which prolonged activation of the mitotic checkpoint affects both tumorigenesis and antimitotic chemotherapy.