Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, worms and flies. Mammals contain seven homologs of yeast Sir2, SIRT1-7. Here, we review recent findings demonstrating the role of these mammalian sirtuins as regulators of physiology, calorie restriction, and aging. The current findings sharpen our understanding of sirtuins as potential pharmacological targets to treat the major diseases of aging.