Vascular injury represents a critical initiating event in the pathogenesis of various vascular diseases, including atherosclerosis. This review discusses 1) the current understanding and a new pathologic classification of vascular injury; 2) the resultant cellular pathophysiologic responses, specifically, lipid accumulation, platelet aggregation, thrombus formation and smooth muscle cell proliferation; 3) the role of vascular injury in the pathogenesis of spontaneous and accelerated atherosclerosis; and 4) emerging therapeutic approaches in preventing these vascular diseases. The process of type I vascular injury (nondenuding functional injury) followed by lipid accumulation, monocyte and platelet adhesion, smooth muscle cell proliferation and resultant plaque formation represents the prevalent view of the early stages of spontaneous atherogenesis. The syndromes of accelerated atherosclerosis (namely, heart transplant atherosclerosis, coronary vein graft disease and restenosis after percutaneous transluminal coronary angioplasty) appear to share etiologic mechanisms with spontaneous atherosclerosis by means of the "response to injury" hypothesis. However, type II and type III vascular injury (denuding endothelial and intimal injury with or without medial damage) followed by thrombus and its organization by smooth muscle cell proliferation and subsequent fibrosis appear to be responsible for the vascular process. This accelerated and premature occlusive process accounts for significant morbidity and mortality in patients with these conditions. Better understanding of the nature of vascular injury and its pathophysiologic responses in these clinical situations may aid in developing therapeutic strategies for preventing these vascular diseases.