p53, a chief tumor suppressor in multicellular organisms, induces cell cycle arrest, DNA repair and apoptosis to promote genomic stability and tissue homeostasis. The function of p53 is normally ascribed to its regulation of numerous p53-responsive genes through direct interactions with both chromatin and regulators of transcription. Nonetheless, evidence exists that p53 has an extranuclear role in the cytoplasm to induce apoptosis. Recently, p53 has been shown to directly activate the pro-apoptotic Bcl-2 protein Bax allowing for mitochondrial membrane permeabilization and apoptosis. In parallel, p53 can release pro-apoptotic Bcl-2 proteins sequestered by Bcl-x(L). These data suggest that cytoplasmic p53 functions analogously to the BH3-only proteins, a subset of pro-apoptotic Bcl-2 proteins.