Sir2 is a NAD(+)-dependent deacetylase, which regulates life span in multiple model organisms in response to caloric restriction. Mammalian homologues of Sir2 comprise a family of seven proteins termed sirtuins (SIRT1-SIRT7), which have gained considerable attention for their impact on several important physiological processes associated with metabolism and stress resistance. In addition, recent studies point to SIRT1 as a key regulator of vascular endothelial homeostasis controlling angiogenesis, vascular tone and endothelial dysfunction. Here, we review the emerging role of SIRT1 as an important modulator of signaling networks critical for maintaining vascular endothelial homeostasis and discuss SIRT1 as a potential therapeutic target for cardiovascular diseases in the adult.