Vascular smooth muscle cell (VSMC) differentiation and proliferation are two important physiological proc?esses during vascular development. The phenotypic alteration from differentiated to proliferative VSMC contrib?utes to the development of several major cardiovascular diseases including atherosclerosis, hypertension, resteno?sis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. Since the VSMC phenotype in these pathological conditions resembles that of developing VSMC during embryonic development, understanding of the molecular mechanisms that control VSMC differentiation will provide fundamental insights into the pathological processes of these cardiovascular diseases. Although VSMC differentiation is usually ac?companied by an irreversible cell cycle exit, VSMC proliferation and differentiation occur concurrently during embryonic development. The molecular mechanisms simultaneously regulating these two processes, however, remain largely unknown. Our recent study demonstrates that cell division cycle 7, a key regulator of cell cycle, promotes both VSMC differentiation and proliferation through different mechanisms during the initial phase of VSMC differentiation. Conversely, Krüppel-like factor 4 appears to be a repressor for both VSMC differentia?tion and proliferation. This review attempts to highlight the novel role of cell division cycle 7 in TGF-β-induced VSMC differentiation and proliferation. The role of Krüppel-like factor 4 in suppressing these two processes will also be discussed.