The endothelium plays a major role in modulating vascular smooth muscle tone by synthesizing and metabolizing a number of vasoactive substances. Since the endothelium is both a target for and a mediator of vascular disease, functional alterations in coronary vascular reactivity due to endothelial dysfunction might play an important integral part in the clinical presentation of coronary artery disease. Recent advances in interventional techniques including intracoronary instrumentation by Doppler catheters to measure blood flow velocities and 2-D-ultrasound catheters to evaluate arterial wall architecture during coronary angiography provided the diagnostic tools to assess endothelial vasodilator function and its relation to atherosclerotic disease. The current weight of evidence suggests that disturbances of vasomotor function of epicardial conductance vessels are fundamental to the development of atherosclerosis, and impaired endothelial vasodilation is the predominant mechanism underlying inappropriate vasoconstriction in atherosclerosis. However, endothelial vasodilator dysfunction is not only confined to atherosclerotic epicardial vessels, but may also extend into the coronary microcirculation, which does not develop overt atherosclerotic lesions, but determines coronary blood flow in the absence of hemodynamically significant stenoses. The most important factors associated with impaired endothelium-mediated dilation of the coronary microcirculation are hypercholesterolemia and advanced age. With respect to the clinical presentation of coronary artery disease, endothelial vasodilator dysfunction appears to play a causative role for triggering myocardial ischemia in stable angina pectoris, to aggravate the sequelae of acute ischemic syndromes, and might be the primary underlying mechanism in some patients with syndrome X, whereas variant angina appears to be related to a hyperreactivity of the vascular smooth muscle layer. Thus, the assessment of endothelium-mediated modulation of coronary vasomotor tone in the clinical setting offers unique and important insights into mechanisms leading to ischemic manifestations of coronary artery disease.