Vascular smooth muscle cell proliferation plays a major role in the development of numerous vascular pathologies. Understanding the molecular mechanisms that regulate smooth muscle cell proliferation is therefore essential for the development of new therapies for the treatment of these pathologies. Skp2 is an F-box protein component of the SCFSkp2 ubiquitin-ligase that controls cellular proliferation by regulating the ubiquitination and degradation of several cell-cycle regulatory proteins, including the cyclin-dependent kinase inhibitor, p27Kip1. This review discusses the recent literature on the function and regulation of Skp2 in smooth muscle cells, which is emerging as a key player in the control of smooth muscle cell proliferation during vascular disease.