Cancer biology finds itself in a post-genomic era and the hopes of using inherited genetic variants to improve prevention and treatment strategies are widespread. One of the largest types of inherited genetic variation is the single nucleotide polymorphism (SNP), of which there are at least 4.5 million. The challenge now becomes how to discover which polymorphisms alter cancer in humans and how to begin to understand their mechanism of action. In this report, a series of recent publications will be reviewed that have studied a polymorphism in the p53 tumor suppressor pathway, MDM2 SNP309. These reports have lent insights into how germline genetic variants of the p53 pathway could interact with gender, environmental stresses and tumor genetics to affect cancer in humans. Importantly, these observations have also exposed potential nodes of intervention, which could prove valuable in both the prevention and treatment of this disease in humans.