Sirtuin 1 (SIRT1), the mammalian ortholog of yeast Sir2p, is a highly conserved NAD+-dependent protein deacetylase that has emerged as a key cardiometabolic regulator. During the past decade, Sir2p has been the focus of intense investigations and discussion because it regulates longevity in yeast, worms and flies. Although the extrapolation of data obtained from yeast Sir2p to mammalian SIRT1 cannot be automatic, animal studies provide convincing evidence that SIRT1 is a potent protector against aging-associated pathologies, in particular metabolic disorders and cardiovascular diseases. Indeed, many exciting connections exist between the protein deacetylation function of SIRT1 and its role in fundamental biological responses to various nutritional and environmental signals. As a result, pharmaceutical and nutriceutical interventions targeting SIRT1 are promising strategies to combat aging-associated diseases. The present review summarizes the recent progress in SIRT1 research with a particular focus on the specificities of this protein in individual tissues as they relate to cardiometabolic control.