The tumor suppressor p53 is a transcription factor and is activated in response to DNA damage or oncogenic transformation through modification of its interaction with regulatory proteins. The transcription factor activity of p53 is thought to mediate its primary functions of cell-cycle arrest and apoptosis through the gene expression it regulates, and evidence to support this interpretation continues to accumulate. However, reports of transcription-independent activities of p53, especially in the induction of apoptosis, persist. In particular, recent studies suggest that cytosolic p53 directly interacts with members of the BCL-2 family of apoptosis regulators, thereby triggering mitochondrial outer membrane permeabilization and apoptosis. In this article, we examine the possible relationships between the transcription-dependent activity of p53 and its transcription-independent activity, and we propose ways in which both might regulate apoptosis.