It is now well established that p53 is the primary arbiter of stress-response and the principal barrier to neoplastic processes at the cellular level. Perhaps the most potent weapon in p53's tumor suppressive arsenal is apoptosis, enacted as a last resort when all other remedies are exhausted. Initially, the mechanism was thought to be simply activation or repression of Bcl-2 family members by p53. More recently, evidence of a more rapid pathway emerged whereby p53 physically interacts with Bcl-2 family members to tip the balance toward apoptosis. This review details the multiple levels of regulation of mitochondrially-directed apoptosis by p53, including recent findings of how p53 translocation is regulated.