The p53 tumor suppressor is a multifaceted transcription factor that responds to a diverse array of stresses that include DNA damage and aberrant oncogene signaling. On activation, p53 prevents the emergence of cancer cells by initiating cell cycle arrest, senescence (terminal cell cycle arrest), or apoptosis. Although its role in assuring longevity by suppressing cancer is well established, recent studies obtained largely from genetically engineered mouse models suggest that p53 may regulate longevity and aging. In some contexts, it appears that altered p53 activity may enhance longevity, and in others, it appears to suppress longevity and accelerate aging phenotypes. Here, we discuss how genetically engineered mouse models have been used to explore antiproliferative functions of p53 in cancer suppression and how mouse models with altered aging phenotypes have shed light on how p53 might influence the aging process.