Apoptosis is now recognized as an important process in tissue homeostasis. In malignancy, mutations in apoptotic programs may promote tumor progression as well as reduce the efficacy of cancer therapy. Recent studies identify the product of the p53 tumor-suppressor gene as an important regulator of apoptosis in tumor cells. At the same time, clinical studies implicate p53 mutations in pleiotropic resistance to cytotoxic cancer therapy. Together, these observations suggest that inactivation of p53 promotes resistance to anticancer agents by attenuating apoptosis. This view identifies p53 as a potential drug target and suggests several strategies for therapeutic intervention.