The International Agency for Research on Cancer estimates that 25% of cancer cases worldwide are caused by overweight or obesity and a sedentary lifestyle. These lifestyle patterns may increase cancer risk by several mechanisms including increased estrogens and testosterone, hyperinsulinemia and insulin resistance, increased inflammation, and depressed immune function. Several randomized clinical trials have shown that physical activity and diet interventions can change biomarkers of cancer risk. In a controlled physical activity trial, we found decreases in serum estrogen, testosterone, and insulin in overweight, sedentary postmenopausal women with a 1-y exercise program consisting of moderate-intensity aerobic exercise, 45 min/d, 5 d/wk. In another controlled trial in middle-aged to older persons, we found that a 1-y exercise intervention of 60 min/d, 6 d/wk, reduced colon crypt cell proliferation in men who adhered closely to the program. Only 1 trial, the Women's Health Initiative Dietary Modification Trial, has published results of a dietary intervention on breast cancer incidence and reported a statistically nonsignificant 9% reduction in invasive breast cancer incidence in postmenopausal women following a low-fat dietary pattern for 8-12 y. Other trials under way are testing effects of weight loss, physical activity, and dietary patterns on other cancer biomarkers. The NCI-funded Transdisciplinary Research on Energetics and Cancer centers are exploring novel research into mechanisms linking energy balance with cancer risk and prevention. The worldwide trends toward increasing overweight and obesity and decreasing physical activity may lead to an increased incidence of several cancers unless other means of risk reduction counteract these effects. Thus, adoption of lifestyle changes by individuals and populations may have a large impact on the future incidence of cancer.