Animal experiments have shown that calorically restricted (CR) animals weigh less and live longer than their ad libitum-fed peers. Are these observations applicable to human beings? This is an important question because the prevalence of obesity in America has increased markedly over recent years. We examine whether there are physiologic effects that occur with CR in humans that could plausibly explain the observed longevity of laboratory animals associated with CR. We also review epidemiologic data from observational and interventional studies on the relationships of caloric intake, energy balance, and weight gain with age-related diseases and longevity. Additionally, data on whether long-term, sustained maintenance of weight loss is feasible, as well as the degree of CR achieved in clinical trials, are summarized. Finally, we provide recommendations regarding further epidemiologic research that will help clarify unanswered questions in these areas.