BACKGROUND: Vascular smooth muscle cells (VSMCs) are mature cells that play critical roles in both normal and aberrant cardiovascular conditions. In response to various environmental cues, VSMCs can dedifferentiate from a contractile state to a highly proliferative synthetic state through the so-called "phenotypic switching" process. Changes in VSMC phenotype contribute to numerous vascular-related diseases, including atherosclerosis, calcification, and restenosis following angioplasty. Adventitial VSMC progenitor cells also contribute to formation of the neointima. METHODS/RESULTS: Herein, we review both, the roles of VSMC differentiation in vascular diseases, and the in vitro models used to investigate the molecular mechanisms involved in the regulation of VSMC differentiation and phenotype modulation. CONCLUSION; A comprehensive understanding of VSMC behavior in vascular diseases is essential to identify new therapeutic targets for the prevention and treatment of cardiovascular diseases.