Sirtuins are nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases that link protein acetylation, metabolism, aging, and diseases of aging. Sirtuins were initially found to slow aging in lower organisms and more recently shown to mediate many effects of calorie restriction on metabolism and longevity in mammals. This chapter focuses on two key mammalian sirtuins, SIRT1 (which resides mainly in the nucleus) and SIRT3 (which is mitochondrial). I discuss the many protein substrates of these sirtuins and how they determine the metabolic strategy most efficacious under scarce or abundant food supplies. I also discuss the logic by which sirtuins link protein acetylation and metabolism. Finally, I discuss emerging data showing protection by sirtuins against most of the common diseases of aging. It is possible that sirtuins will be novel targets to combat these diseases pharmacologically.