Physicians have long recognized that people differ in their susceptibility to disease. As early as the fifth century, Hippocrates wrote “Some men have constitutions that are like wooded mountains running with springs, others like those with poor soil and little water, still others like land rich in pastures and marshes, and yet others like the bare, dry earth of the plain.” Today, we describe these observations as interindividual variation in disease risk manifested as gene-environment interactions, a notion embodying the concept that heritable traits modify the effects of environmental exposures. The heritable effects of genes in human cancer pathogenesis range from high penetrance with an attendant high likelihood of causing cancer to low-penetrant genes with an attendant increased risk of causing cancer, albeit less likely than that for high-penetrant genes. Nevertheless, the range from low-penetrant to high-penetrant genes is a continuum, and studies in animal models indicate that the effects of highly penetrant genes can be modified by other genes. In humans, high-penetrant genes that cause family cancer syndromes can have a substantial impact in the affected families (eg, Li-Fraumeni syndrome involving germline mutations in the p53 tumor suppressor pathway), but they affect only a small percentage of the population. In contrast, the manifestations of cancer susceptibility genes with less penetrance contribute to common sporadic cancers and, thus, affect a large segment of the population.