Recent reports on mice with systemic overexpression of the tumor-suppressor PTEN (phosphatase and tensin homolog) have expanded our understanding of its physiological functions. Pten transgenic mice present increased energy expenditure, decreased adiposity, improved insulin sensitivity upon high-fat feeding or with aging, and extended lifespan. This has led to new mechanistic insights about the role of PTEN in metabolism. Interestingly, PTEN promotes oxidative phosphorylation and decreases glycolysis, thus preventing the metabolic reprogramming characteristic of cancer cells, which might be relevant to PTEN-mediated cancer protection. PTEN also upregulates UCP1 expression in brown adipocytes, which enhances their nutrient burning capacity and decreases adiposity and associated pathologies. The newly discovered effects of PTEN on metabolism open new avenues for exploration relevant to cancer, obesity, diabetes, and aging.