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Sirtuins are an evolutionarily conserved family of NAD⁺-dependent deacylases that display diversity in subcellular localization and function. SIRT2, the predominantly cytosolic sirtuin, is among the least understood of the seven mammalian sirtuin isoforms described (SIRT1–7). The purpose of this review is to summarize the most recent findings about the potential roles and effects of SIRT2 in mammalian metabolic homeostasis. We discuss the different functions and targets of SIRT2 in various physiological processes, including adipogenesis, fatty acid oxidation, gluconeogenesis, and insulin sensitivity. We also cover the role of SIRT2 in inflammation and oxidative stress due to the possible implications for metabolic disorders. Finally, we consider its potential as a therapeutic target for the prevention and treatment of type 2 diabetes.