During the past decade, it has become clear that the vascular endothelium critically influences vascular permeability, controls vessel growth, modulates hemostasis, and regulates vasomotion. This latter role of the endothelium is mediated by the liberation of a number of potent vasoactive compounds, including endothelium-derived relaxing factors, one of which is either nitric oxide or a compound that releases nitric oxide, vasoactive prostaglandins, hyperpolarizing factors, and a number of constricting factors. This role of the endothelium is dramatically altered by several diseases, including atherosclerosis, hypertension, and diabetes. Abnormalities of endothelial regulation of vascular tone may contribute to a number of clinical syndromes, including variant angina, unstable angina, syndrome X, and perhaps many others. In this review, several aspects of the endothelium-derived relaxing factor will be considered, including recent concepts regarding its synthesis, its chemical identity, and alterations in atherosclerosis. Finally, its action in the coronary microcirculation as contrasted to that of nitroglycerin will be considered.