The vascular smooth muscle cell (SMC) in adult animals is a highly specialized cell whose principal function is contraction. However, this cell displays remarkable plasticity and can undergo profound changes in phenotype during repair of vascular injury, during remodeling in response to altered blood flow, or in various disease states. There has been extensive progress in recent years in our understanding of the complex mechanisms that control SMC differentiation and phenotypic plasticity, including the demonstration that epigenetic mechanisms play a critical role. In addition, recent evidence indicates that SMC phenotypic switching in adult animals involves the reactivation of embryonic stem cell pluripotency genes and that mesenchymal stem cells may be derived from SMC and/or pericytes. This review summarizes the current state of our knowledge in this field and identifies some of the key unresolved challenges and questions that we feel require further study.