The p53 tumor suppressor gene continues to be distinguished as the most frequently mutated gene in human cancer; this gene can be found mutated in up to 50% of human tumors of diverse histological type. It is generally accepted that the ability of p53 to induce either growth arrest or programmed cell death in response to diverse stimuli underlies the powerful selection against this protein in the development of cancer. It is somewhat surprising, then, to find p53 and several target genes in this pathway containing polymorphisms that impair their function. The nature of these polymorphic variants, and the mechanism whereby they impair the function of the p53 pathway, are reviewed here-in. The impact of these polymorphisms on cancer risk and the efficacy of therapy are only now becoming unraveled. Of particular relevance in these efforts will be the generation of mouse models of polymorphic variants in p53 and its target genes. Equally important will be better-controlled human studies, where-in haplotypes for p53 (that is, combinations of different polymorphisms in the p53 gene) and for p53-target genes are taken into account, instead of analyses of single gene variants, which have largely predominated to date. Studies in both regards should shed light on an emerging area in cancer biology, the significance of inter-individual differences in genotype on cancer risk, prognosis, and the efficacy of cancer therapy.