Sirtuins are a highly conserved family of NAD⁺-dependent deacetylase enzymes that have beneficial effects against metabolic and age-related diseases. Accumulating evidence indicates that sirtuins act as important nutrient and energy sensors of the cell, and mediate the key effects of caloric restriction during ageing. Sirtuins are activated by elevated NAD⁺ levels induced during states of high-energy demand, such as fasting, calorie restriction and exercise. To date, seven mammalian sirtuins (SIRT1-SIRT7) has been discovered that vary in tissue specificity, subcellular localization, enzyme activity and targets. SIRT1, SIRT6, and SIRT7 are nuclear proteins, SIRT2 is primarily cytosolic, whereas SIRT3, SIRT4 and SIRT5 are found in mitochondria. Sirtuins deacetylate both histone and non-histone proteins, and by removing the acetyl groups, sirtuins can either activate or inhibit their protein targets. SIRT1 exerts pleiotropic effects of age-related diseases; SIRT1 activation has been shown to decrease susceptibility to oxidative stress and apoptosis, mitigate inflammation, provide neuroprotection, and delay cardiovascular aging. The most important non-histone protein targets that are regulated by SIRT1 in a tissue-specific manner are PGC1-a, NFkB, p53 and eNOS. SIRT3, which is also induced by caloric restriction, targets mitochondrial proteins associated with ATP production, fatty acid oxidation and ROS detoxification. Small molecule activators that biochemically increase the catalytic activity of SIRT1 or SIRT3, and thereby mimic the beneficial effects of caloric restriction, are currently under development. Such compounds could provide a novel pharmacological approach to treat metabolic (type 2 diabetes, obesity) and neurodegenerative diseases in future.