Vascular smooth muscle cell (VSMC) differentiation is an essential component of vascular development. These cells perform biosynthetic, proliferative, and contractile roles in the vessel wall. VSMCs are not terminally differentiated and are able to modulate their phenotype in response to changing local environmental cues. There is clear evidence that alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of atherosclerosis and intimal hyperplasia, as well as in a variety of other major human diseases, including hypertension, asthma, and vascular aneurysms. The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms involved in controlling phenotypic switching of SMCs, with particular focus on examination of signaling pathway that regulate this process.