More than 70 years after its initial report, caloric restriction stands strong as the most consistent non- pharmacological intervention increasing lifespan and protecting against metabolic disease. Among the different mechanisms by which caloric restriction might act, Sir2/SIRT1 (Silent information regulator 2/Silent information regulator T1) has been the focus of much attention because of its ability to integrate sensing of the metabolic status with adaptive transcriptional outputs. This review focuses on gathered evidence suggesting that Sir2/SIRT1 is a key mediator of the beneficial effects of caloric restriction and addresses the main questions that still need to be answered to consolidate this hypothesis.