Restenosis after coronary angioplasty is due to a proliferation of smooth muscle cells growing in the vascular lumen, beneath the residual fragments of the atherosclerotic plaque, as seen in necropsy studies and examination of the specimens removed by atherectomy. At the histological analysis thrombi or their fibrocellular organization are not usually detectable. Smooth muscle cell proliferation leading to restenosis is very similar to the one observed in the experimental models of response-to-injury, so that these models are used to investigate into the pathogenetic mechanisms of restenosis. The main stimulus to the loss of the contractile phenotype and to the start of the smooth muscle cell proliferation is represented by the growth factors delivered by platelets adhered to the disendothelialized wall and by the smooth muscle cells themselves, stretched during the dilatation. Other stimuli can be growth factors delivered by monocytes and fibroblasts, by thrombin, endothelin, angiotensin and interleukin 1. The elastic recoil of the vessel wall, the plaque debris and the regional wall shear stress can also contribute to restenosis. The restenosis tissue is different from the atheromatous plaque in that it is almost only constituted by smooth muscle cells and intercellular matrix, while atheroma is much more complex due to the presence of various kinds of cells, of necrotic debris and lipid substances. The smooth muscle cells proliferation also contributes to the pathogenesis of atherosclerosis, but the stimuli starting this process have not been clarified yet; moreover this process is much slower than restenosis, interacting with several factors. Encouraging results have been achieved in the prevention of restenosis after angioplasty in experimental models, but not in man. In order to reduce the incidence of restenosis one should improve the results of angioplasty, even by the use of atherectomy and intracoronary stents. Among pharmacologic approaches anticoagulants, heparin, antiplatelet agents, calcium-channel blockers, corticosteroids all proved ineffective. Studies are in progress evaluating the effect of inhibitors of platelet-derived growth factor (PDGF), antitumor agents and radiation therapy, hirudin, angiotensin-converting enzyme inhibitors and HMG-CoA reductase inhibitors.