Most living organisms, including humans, age. Over time the ability to do physical and intellectual work deteriorates, and susceptibility to infectious, metabolic, and neurodegenerative diseases increases, which leads to general fitness decline and ultimately to death. Work in model organisms has demonstrated that genetic and environmental manipulations can prevent numerous age-associated diseases, improve health at advanced age, and increase life span. Calorie restriction (CR) (consumption of a diet with fewer calories but containing all the essential nutrients) is the most robust manipulation, genetic or environmental, to extend longevity and improve health parameters in laboratory animals. However, outside of the protected laboratory environment, the effects of CR are much less certain. Understanding the molecular mechanisms of CR may lead to the development of novel therapies to combat diseases of aging and to improve the quality of life. Sirtuins, a family of NAD(+)-dependent enzymes, mediate a number of metabolic and behavioral responses to CR and are intriguing targets for pharmaceutical interventions. We review the molecular understanding of CR; the role of sirtuins in CR; and the effects of sirtuins on physiology, mood, and behavior.