In the 75 years since the seminal observation of Clive McCay that restriction of calorie intake extends the lifespan of rats, a great deal has been learned about the effects of calorie restriction (CR; reduced intake of a nutritious diet) on aging in various short-lived animal models. Studies have demonstrated many beneficial effects of CR on health, the rate of aging, and longevity. Two prospective investigations of the effects of CR on long-lived nonhuman primate (NHP) species began nearly 25 years ago and are still under way. This review presents the design, methods, and main findings of these and other important contributing studies, which have generally revealed beneficial effects of CR on physiological function and the retardation of disease consistent with studies in other species. Specifically, prolonged CR appears to extend the lifespan of rhesus monkeys, which exhibited lower body fat; slower rate of muscle loss with age; lower incidence of neoplasia, cardiovascular disease, type 2 diabetes mellitus, and endometriosis; improved insulin sensitivity and glucose tolerance; and no apparent adverse effect on bone health, as well as a reduction in total energy expenditure. In addition, there are no reports of deleterious effects of CR on reproductive endpoints, and brain morphology is preserved by CR. Adrenal and thyroid hormone profiles are inconsistently affected. More research is needed to delineate the mechanisms of the desirable outcomes of CR and to develop interventions that can produce similar beneficial outcomes for humans. This research offers tremendous potential for producing novel insights into aging and risk of disease.