SIRT6 is one of the seven members of the NAD-dependent family of sirtuins mammals. The pleotropic identity of SIRT6 is manifested into several catalytic activities such as deacetylation, deacylation and ribosylation, which allow the targeting of a variety of protein substrates, that influence the physiology of multiple cell types and tissues. SIRT6- dependent deacetylation of histone H3 at lysines 9 and 56 is required for the regulation of genes associated with glucose/ lipid metabolism as well as the maintenance of telomeric regions and the repair of DNA double strand breaks. Importantly, SIRT6 depletion alters the levels of acetylated histone H3 causing a deregulation of genes involved in glycolysis and the Myc-target network, which results in tumorigenesis. Hence, SIRT6 has been recently categorized as a tumor suppressor. The deacylation activity of SIRT6 has been attributed to the regulation of TNF-α secretion. However, the physiological relevance of this newly discovered catalytic activity of SIRT6 remains to be determined in vivo. SIRT6 also undergoes auto-ribosylation, which might contribute to a self-regulation of catalytic functions. SIRT6-mediated ribosylation also enhances PARP1-dependent DNA repair under oxidative stress and aging. Overall, SIRT6 is a critical enzyme required to maintain glucose/lipid homeostasis and genomic stability, thereby promoting resistance to oxidative stress and DNA damage, which are associated to age-related illness. Evocative of its ancestor, yeast Sir2, SIRT6 has the ability to increase lifespan in mice. SIRT6 deficiency is associated with various diseases including inflammation, cardiac hypertrophy, liver dysfunction, adipocyte/muscle disorders, and cancer. This review describes the most current information regarding the molecular and physiological relevance of SIRT6 in the context of epigenetics, metabolism and disease.