Candidate gene association studies to detect breast cancer susceptibility loci have yielded few positive associations. Therefore, it is more likely that variants in many genes along related biological pathways combine to influence breast cancer risk. A strong candidate pathway is that of p53-mediated cell-cycle control, DNA repair, and apoptosis. The two major proteins along this pathway are p53 and its negative regulator MDM2. Functional polymorphisms in both genes have been identified. The -309 SNP in MDM2 is associated with increased MDM2 transcription. The Arg72Pro polymorphism of p53 alters the transcription of p53 target genes and modifies the apoptotic potential of cells. Both polymorphisms have been studied with respect to breast cancer risk, with inconclusive results. We have genotyped both polymorphisms in the breast cancer cases and controls nested within the Nurses' Health Study and Nurses' Health Study II. Neither SNP is independently associated with overall breast cancer risk. Some indication of gene-by-gene interaction was observed; however, no consistent direction of interaction was apparent.