Induction of apoptosis is an essential function of p53 as a tumor suppressor. p53 can activate its downstream targets in a sequence specific manner to induce apoptosis. Most tumor derived p53 mutants are deficient in transcription activation as well as apoptosis induction. p53 can activate genes in the extrinsic and intrinsic pathways through transcription-dependent mechanisms or induce apoptosis through transcription-independent mechanisms. Several proapoptotic Bcl-2 family proteins, such as PUMA and Noxa, are shown to be critical mediators of p53-dependent apoptosis. The selective activation of the apoptotic targets of p53 is modulated by transcription coactivators. The induction of apoptotic genes alone sometimes is not sufficient to induce apoptosis, as the cell cycle arrest mediated by the cell cycle inhibitors dominates apoptosis. Preventing the induction of p21 under these conditions can drive the cells towards apoptosis. Understanding how p53 controls apoptosis through its targets may lead to discoveries of novel therapeutics to combat cancer and other diseases.