Calorie restriction (CR) mimetics are agents or strategies that can mimic the beneficial health-promoting and anti-aging effects of CR, the only intervention conclusively shown to slow aging and maintain health and vitality across the phylogenetic spectrum. Our lead compound, developed at the National Institute on Aging, was 2-deoxyglucose, an analogue of the native sugar, that acted as a glycolytic inhibitor, having limited metabolism and actually reducing overall energy flow--analogous to CR. This agent reduced insulin levels and body temperature of rats, similar to the physiological effects of CR, but toxicity was noted in long-term studies, which apparently prevented life-span extension. We previously demonstrated that lower insulin and body temperature (as well as maintenance of dehydroepiandrosterone levels) correlate with longevity in non-CR humans. The recent work of other investigators shows that humans subjected to short-term CR also have lower insulin and body temperature. Obviously, longer-term CR is extremely difficult to maintain; hence, the need for CR mimetics. The next phase of calorie restriction studies includes basic investigations as well as possible clinical trials of a number of candidate CR mimetics, ranging from glycolytic inhibitors to lipid-regulating agents to antioxidants and specific gene modulators. The scope of these ongoing studies in various laboratories, as well as their practical implications, are reviewed and analyzed here.