By applying calorie restriction (CR) at 30-50% below ad libitum levels, studies in numerous species have reported increased lifespan, reduced incidence of age-related diseases, improved stress resistance, and decelerated functional decline. Whether this nutritional intervention is relevant to human aging remains to be determined; however, evidence emerging from CR studies in nonhuman primates suggests that response to CR in primates parallels that observed in rodents. To evaluate CR effects in humans, clinical trials have been initiated. Even if evidence could substantiate CR as an effective anti-aging strategy for humans, application of this intervention would be problematic due to the severity and length of restriction required. To meet this challenge for potential application of CR, new research termed "caloric restriction mimetics" has emerged. This strategy focuses on identifying compounds that mimic CR effects by activating stress response pathways enhanced by CR, but without actually restricting caloric intake. Drugs that inhibit glycolysis (2-deoxyglucose) or enhance insulin action (metformin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiological responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicicty, enhanced dopamine action, and upregulated brain-derived neurotrophic factor. Further lifespan analyses in addition to expanded toxicity studies must be completed to assess the potential of any CR mimetic, but this strategy now appears to offer a very promising and expanding research field.