The prevalence of mutations that inactivate the p53 tumor suppressor gene in human cancers reveals the importance of p53 in preventing cancer. Recent progress has generated increased enthusiasm for re-activating p53 in tumors with mutant p53 proteins as well as for increasing p53 function in tumors expressing wild-type p53 that is inhibited in trans. However, excessive p53 activity can be detrimental to the host, potentially limiting the utility of p53 activation as a therapeutic strategy. For example, uncontrolled p53 activity is lethal to the murine embryo, and p53 has been associated with increased aging in people and mice. Here we review the literature linking p53 to aging and discuss reports demonstrating that p53 can suppress tumor formation without accelerating aging. We raise the possibility that activation of p53 remains a promising strategy for cancer chemoprevention and therapy even if, under some circumstances, p53 might accelerate aging.