P53-mediated apoptosis of cells with DNA damage or oncogene overexpression is a major mechanism for its function as a tumor suppressor. Both transcriptionally dependent and transcriptionally independent activities of p53 can play a role in mediating cell death. It appears that p53 can induce apoptosis by multiple pathways in a manner which is regulated in a cell type and signal-specific fashion. Understanding the biochemical mechanisms of p53-dependent apoptosis holds a promise of manipulating these pathways in cancer therapy.