The majority of human cancers result from exposure to environmental carcinogens. Epidemiologic studies, as well as studies in animal models of cancer, have demonstrated a wide range of responses to carcinogen exposure and it is now clear that common allelic variants within the genome are responsible for this interindividual variation. Identification of specific genes that modify the response to carcinogen exposure has been difficult. However, new approaches in both human and animal studies have improved the likelihood that cancer modifier genes will be identified. Importantly, many of the modifier genes identified in animal models have been shown to modify cancer risk in humans, demonstrating the utility of animal studies. The identification of cancer modifier genes will ultimately lead to the development of new cancer risk models, the detection of individuals at high risk for cancer development, and improved prevention strategies.