Recent findings demonstrate that adventitial fibroblasts (i.e., nonmuscle cells) are endowed with several characteristics previously attributed to medial SM cells. The response of the coronary artery to balloon angioplasty is associated with the activation of adventitial cells in a porcine model. They appear to be the most reactive in the arterial wall, as reflected by the extent of proliferation and the synthesis of collagen. Differentiation of adventitial cells, which acquire alpha-SM actin, illustrates the formation of vascular myofibroblasts, a ubiquitous cellular mechanism of tissue repair. Myofibroblasts are involved in remodeling of the adventitia and may contribute to the formation of the neointima after balloon-induced coronary injury. These findings suggest that at least some synthetic SM-like cells present in intimal lesions may originate from medial or adventitial nonmuscle cells. Myofibroblasts also appear to play a role in other cardiovascular abnormalities (e.g., vein graft remodeling), which raises the possibility of targeted therapies.