Sirt1 is a type III histone deacetylase implicated in a wide range of physiological and pathophysiological roles. Acting though a myriad of non-histone substrates, Sirt1 modulates transcriptional regulation of energy metabolism and stress response, with important consequences on cell survival and a myriad of human pathologies. Sirt1 has an apparent (albeit context- and tissue type-dependent) role in tumorigenesis, acting particularly through its deacetylation of tumor suppressor gene products such as p53 and Rb. Recent works have now revealed that cortactin, an F-actin binding protein with established roles in protrusive actin dynamics, is a Sirt1 substrate. Cortactin could be acetylated by the acetyltransferase p300, and its deacetylation by Sirt1, either directly or indirectly, retards cell migration. In conjunction with deacetylation of other oncogenic targets, Sirt1's modulation of cell migration and invasion may be an important additional aspect of its tumorigenic activity.