Atherosclerotic lesions take two forms, the fatty streak and the fibrous plaque or complicated lesion. The former is a flat, lipid-rich lesion containing variable numbers of foam cells in the form of macrophages and/or smooth muscle. In contrast, the fibrous plaque is a proliferative lesion of smooth muscle containing variable numbers of macrophages. Associated with the smooth muscle proliferative response is the formation of connective tissue matrix and the accumulation of intracellular and extracellular lipid. The response to injury hypothesis of atherogenesis provides and approach to exploring the interactions among substances that alter endothelial function and/or structure and to investigating the relationships among endothelium, smooth muscle, platelets, macrophages, and plasma constituents. Studies of molecules potentially important in lesion development, such as mitogens derived from platelets, macrophages, and endothelium, and of the potential roles of lipids in generating these lesions and in inducing injury to the overlying endothelial cells, have begun to shed light on how these processes may occur and on approaches that may be taken to better understand and possibly prevent them. We still lack an understanding of one of the key events, endothelial injury. The many ways by which endothelial cells may be altered in relation to the hypercholesterolemic environment and to the underlying macrophages in the fatty streaks remain to be explored. Nevertheless, these approaches point the way to the development of new means for prevention, intervention, and diagnosis of atherosclerosis.