Differentiation of vascular smooth muscle cells (VSMC) is an essential process of vascular development. VSMC have biosynthetic, proliferative, and contractile roles in the vessel wall. 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 human diseases, including hypertension, asthma, atherosclerosis and vascular aneurysm. This review provides an overview of the current state of knowledge of molecular mechanisms involved in controlling VSMC proliferation, with particular focus on glucose metabolism and its relationship with mitochondrial bioenergetics. Increased levels of glucose transporter 1 (GLUT1) are observed in VSMC after endothelial injury, suggesting a relationship between glucose uptake and VSMC proliferation. Mitochondrial dysfunction is a common feature in VSMC during atherosclerosis. Alterations in mitochondrial function can be produced by dysregulation of mitofusin-2, a small GTPase associated with mitochondrial fusion. Moreover, exacerbated proliferation was observed in VSMC from pulmonary arteries with hyperpolarized mitochondria and enhanced glycolysis/glucose oxidation ratio. Several lines of evidence highlight the relevance of glucose metabolism in the control of VSMC proliferation, indicating a new area to be explored in the control of vascular pathogenesis.