Calorie restriction (CR) remains the most robust environmental intervention for altering aging processes and increasing healthspan and lifespan. Emerging from progress made in many nonhuman models, current research has expanded to formal, controlled human studies of CR. Since long-term CR requires a major commitment of will power and long-term negative consequences remain to be determined, the concept of a calorie restriction mimetic (CRM) has become a new area of investigation within gerontology. We have proposed that a CRM is a compound that mimics metabolic, hormonal, and physiological effects of CR, activates stress response pathways observed in CR and enhances stress protection, produces CR-like effects on longevity, reduces age-related disease, and maintains more youthful function, all without significantly reducing food intake. Over 12 years ago, we introduced the concept of glycolytic inhibition as a strategy for developing mimetics of CR. We have argued that inhibiting energy utilization as far upstream as possible might offer a broader range of CR-like effects as opposed to targeting a singular molecular target downstream. As the first candidate CRM, 2-deoxyglucose, a known anti-glycolytic, provided a remarkable phenotype of CR, but turned out to produce cardiotoxicity in rats. Since the introduction of 2DG as a candidate CRM, many different targets for development have now been proposed at more downstream sites, including insulin receptor sensitizers, sirtuin activators, and inhibitors of mTOR. This review discusses these various strategies to assess their current status and future potential for this emerging research field.