We present the hypothesis that high wall stress and accompanying stretch, particularly that caused by arterial pressure, are the primary factors responsible for the topography of atherosclerotic lesions. In our view the pattern in the localization of atherosclerotic lesions indicates that the artery behaves as both a pressure vessel and a conduit of blood flow. The phenomenon of "stress concentration" in the artery wall is described and the area of pressure-induced high stress is related to the sites of atherosclerotic plaques. Data are presented indicating that reduction of pressure-induced stress may lead to absence of atherosclerotic changes. The proposed mechanism explains the prevalence of atherosclerotic lesions at the ostia of major arterial branches, at the aortic bifurcation, at the carotid bifurcation, and in the descending thoracic aorta, and also explains the absence of atherosclerosis in the intramyocardial coronary arteries and in the intraosseal portions of the vertebral vessels and why a reduction in heart rate, blood pressure, or wall stress by external support reduces the occurrence of atherosclerosis. The effect of wall stress and stretch on atherosclerosis could be mediated by the endothelial cells, the smooth muscle cells, and the penetration of low-density lipoproteins. The comprehensive presentation made in this article could lead to a better understanding of atherosclerosis, its treatment, and its prevention.