Studies in mice and rats show that caloric restriction (CR) without malnutrition lowers the incidence of most spontaneous and induced tumors and delays their onsets. The maximum life spans of rodents and other experimental animals (e.g., fish, spiders, water fleas) are extended by CR. The molecular events that underlie these outcomes remain unelucidated. Although epidemiologic studies have not usually examined the relationship between caloric intake and cancer incidence, recent findings suggest a positive association for certain cancers such as colorectal, breast, and stomach. It is apparent that future studies of diet and cancer in humans must seriously assess the role of calories and energy balance as well as their interaction with the effects of specific nutrients.