The endothelium plays a crucial role in the regulation of coronary artery vasomotor tone by conducting stimuli from the blood into changes of vascular smooth muscle tone. Disturbance of this endothelial function might inadequately reduce myocardial oxygen supply, and, therefore, contribute to myocardial ischemia. Different risk factors for coronary artery disease are accompanied by a reduced bioactivity of vasorelaxing nitric oxide (NO), produced by the endothelium. In hypercholesterolemia, oxidized LDL and vascular wall macrophages induce an oxidative stress with increased production of superoxide anions, capable to inactivate NO. Therefore, NO-mediated vasorelaxation is blunted in epicardial arteries as well as in the microcirculation. In case of sympathetic stimulation, e.g. by physical exercise or cold exposure, the direct vasoconstrictor action of catecholamines on the vascular smooth muscle cells might dominate due to reduced bioactivity of NO. Especially, in the presence of coronary stenoses, myocardial ischemia might be aggravated. Although "exogenous" NO, derived from nitrates, also relaxes coronary vessels, these drugs are not able to simulate the physiological, demand-adjusted endothelial production of "endogenous" NO. In contrast, following a 6 months therapy with HMG-CoA-reductase inhibitors, impairment of endothelium-dependent vasorelaxation could be improved. In addition, ACE-inhibitors have been shown to ameliorate endothelium-mediated coronary vasodilator function. However, whether improved endothelium-dependent vasodilator function due to ACE-inhibitor or HMG-CoA-reductase inhibitor therapy relate to the improved coronary mortality observed with these drugs, remains to be determined.