The endothelium can respond to a local environment by releasing a variety of substances that regulate the level of vascular tone. One of the most important of these vasoregulatory substances is EDRF. The function of the endothelium is altered in a variety of pathologic and physiologic conditions. This review focused on the role of risk factors for atherosclerosis as it relates to EDRF. Atherosclerotic blood vessels respond abnormally on exposure to stimuli that release EDRF. It is now also apparent that this abnormal vascular response may precede the development of significant atherosclerosis and that normalization of the EDRF response with treatment is possible. Thus abnormal endothelium-dependent relaxation has been demonstrated in hypercholesterolemic patients with little or no evidence of coronary angiographic disease and in patients with hypertension before the development of atherosclerosis. The interaction between risk factors and the function of the vascular endothelium with development of atherosclerosis may become a useful focus for therapies that benefit patient outcomes.