The established role of APC in regulating microtubules and actin in polarized epithelia naturally raises the possibility that APC similarly influences the mitotic cytoskeleton. The recent accumulation of experimental evidence in mitotic cells supports this supposition. APC associates with mitotic spindle microtubules, most notably at the plus-ends of microtubules that interact with kinetochores. Genetic experiments implicate APC in the regulation of spindle microtubule dynamics, probably through its interaction with the microtubule plus-end binding protein, EB1. Moreover, functional data show that APC modulates kinetochore-microtubule attachments and is required for the spindle checkpoint to detect transiently misaligned chromosomes. Together this evidence points to a role for APC in maintaining mitotic fidelity. Such a role is particularly significant when considered in the context of the chromosome instability observed in colorectal tumors bearing mutations in APC. The prevalence of APC truncation mutants in colorectal tumors and the ability of these alleles to act dominantly to inhibit the mitotic spindle place chromosome instability at the earliest stage of colorectal cancer progression (i.e., prior to deregulation of beta-catenin). This may contribute to the autosomal dominant predisposition of patients with familial adenomatous polyposis to develop colon cancer. In this chapter, we will review the literature linking APC to regulation of mitotic fidelity and discuss the implications for dividing epithelial cells in the intestine.