To determine if the effect of nutritional interventions differs by genetic susceptibility to cancer, we must have both an effective intervention as well as a documented marker of genetic susceptibility. The first large clinical trials to test nutritional intervention strategies have recently been reported, and apparent efficacy has been observed for selected antioxidants in the primary prevention of several cancers, including esophageal, stomach, prostate, and colorectal cancers. At the same time, increasing numbers of markers of genetic susceptibility are being identified. Although susceptibility markers have not yet been evaluated in the context of nutritional interventions in humans, preliminary data in animals indicate that calorie restriction reduces spontaneous tumor mortality in p53-knockout mice. Linking the results from nutritional interventions in humans with markers of genetic susceptibility will allow us to better understand gene-environment interactions.