We have tried to compare the proliferative responses seen in two vascular diseases: atherosclerosis and hypertension. Both diseases involve endothelial injury and proliferation, but our knowledge of this phenomenon is just beginning to emergy. In atherosclerosis the best evidence is that denudation does not occur in the normal young animal. Man, however, ages over a much longer time than our usual animal models, and the study of denudation during the chronic progression of atherosclerotic lesions remains to be done. We need to consider the possibility that repetitive, small lesions may occur at sites of endothelial turnover. We also need to know more about the possible role of nondenuding injuries, including death of endothelial cells in situ and the apparent increased stickiness of endothelial cells and monocytes during the early stages of hypercholesterolemia. The role of endothelial injury in hypertension also needs more study. We know that extensive denudation and thrombosis occur in small vessels subjected to high blood pressure. It is highly probable that release of PDGF occurs at these sites, possibly accounting for the characteristic hyperplasia seen in malignant hypertension. Whether this process is related to the more subtle changes in vessel wall mass seen in chronic hypertension remains unknown. Finally, there are remarkable differences in the proliferative behavior of the smooth muscle cells themselves in these two diseases. Hypertensive vascular disease is, in large part, a disease of the media. Atherosclerosis is characterized by intimal hyperplasia. Injury results in migration of smooth muscle cells from the media and cell division in the intima. It is possible to identify chemotactic factors using putative atherosclerosis risk factors or normal components of serum. This has already been done for one component of lesion formation, PDGF, 134 and there is a report of a monocyte chemotactic factor released by smooth muscle cells. 143 Factors released by other components of lesions may be of considerable interest. In contrast, changes in hypertension occur within a more orderly preservation of vessel wall structure. The wall thickens, but this occurs by increased synthesis of cell mass in the media. The cells themselves do not even divide, but they undergo a form of amitotic replication of their DNA. This results in an increase in the protein synthetic apparatus of the vessel wall without any change in cell number and, presumably, with preservation of mechanical and electrochemical connections between cells. Many open questions exist about this observation. We do not know the distribution of polyploid cells in the microvasculature or the fate of polyploid cells in animals undergoing therapy. These are critical issues if we are to consider the possibility that endoreplication is an etiologic event in increasing resistance to flow. We also need to understand why the same cell undergoes true replication in response to one set of stimuli, that is, trauma or action of the PDGF, but endoreplicates in hypertension. Finally, we should return to our opening paragraph. The similarities and relationships between the two major vascular diseases are striking. The search for understanding of common principles underlying the response of all vessels to injury may lead to valuable new directions.