Reduced energy intake, or caloric restriction (CR), is known to extend life-span and to retard age-related health decline in a myriad of species, including nematode worms, flies, fish, mice and rats. The exact mechanism whereby CR exerts its life-extending and health-extending effects is unclear. CR however has been shown to improve insulin sensitivity, reduce oxidative stress and alter neuroendocrine responses and central nervous system (CNS) function in animals. In this review article we provide a comprehensive overview of the effects of CR on animal physiology and we discuss some of the potential molecular mechanisms and pathways whereby reduced energy intake can increase health-span and life-span. A better understanding of how energy intake can influence the aging process could lead to new strategies and therapeutics to reduce age-related decline and increase health-span.