Background Calorie Restriction (CR) research has expanded rapidly over the past few decades and CR remains the most highly reproducible, environmental intervention to improve health and extend lifespan in animal studies. Although many model organisms have consistently demonstrated positive responses to CR, it remains to be shown whether CR will extend lifespan in humans. Additionally, the current environment of excess caloric consumption and high incidence of overweight/obesity illustrate the improbable nature of the long-term adoption of a CR lifestyle by a significant proportion of the human population. Thus, the search for substances that can reproduce the beneficial physiologic responses of CR without a requisite calorie intake reduction, termed CR mimetics (CRMs), has gained momentum. Material and methods Recent articles describing health and lifespan results of CR in nonhuman primates and short-term human studies are discussed. Additional consideration is given to the rapidly expanding search for CRMs. Results The first results from a long-term, randomized, controlled CR study in nonhuman primates showing statistically significant benefits on longevity have now been reported. Additionally, positive results from short-term, randomized, controlled CR studies in humans are suggestive of potential health and longevity gains, while test of proposed CRMs (including rapamycin, resveratrol, 2-deoxyglucose and metformin) have shown both positive and mixed results in rodents. Conclusion Whether current positive results will translate into longevity gains for humans remains an open question. However, the apparent health benefits that have been observed with CR suggest that regardless of longevity gains, the promotion of healthy ageing and disease prevention may be attainable. © 2010 Stichting European Society for Clinical Investigation Journal Foundation.