The p53 tumor suppressor gene enhances longevity by inhibiting cancer development. However, Van Heemst et al. in this issue show that polymorphisms in the p53 gene may affect longevity in unexpected ways. A meta-analysis indicates that individuals homozygous for the p53 codon 72 Pro allele instead of the more prevalent Arg allele have a modest increase in cancer incidence. This difference in cancer suspectibility is consistent with molecular studies showing that the p53 Pro polymorphic variant is a less robust anti-proliferative molecule than its Arg counterpart. The most surprising result was obtained in a prospective study of individuals age 85 or older. Despite having a 2.5-fold increased cancer incidence, the p53 codon 72 Pro/Pro individuals exhibited a significant 41% enhanced survival compared to codon 72 Arg/Pro and Arg/Arg individuals. These paradoxical findings suggest that p53 may enhance survival through most of our life span, but may actively suppress longevity during old age. The mechanisms for such duplicity remain unclear, but insights from p53 mutant mouse models may help to sort out the mystery.