During the past 8 years, it has become apparent that endothelium-dependent vascular relaxation is abnormal in a variety of disease states, including hypercholesterolemia, atherosclerosis, diabetes, hypertension, and following heart transplantation. Our laboratory and several others have examined dysfunctional regulation of vasomotor tone in hypercholesterolemia and atherosclerosis. These studies have led to the concepts that altered regulation of vasomotion by the endothelium (1) is an early development in atherosclerosis, (2) involves both large vessels (with overt atherosclerosis) and the microcirculation (in which atherosclerosis does not develop), and (3) can be reversed by lipid-lowering strategies. The mechanisms for the abnormalities underlying this form of endothelial dysfunction are likely multifactorial, but a major underlying factor appears to be increased oxidant degradation of endothelium-derived nitric oxide. In this review we examine the evidence supporting this conclusion and consider the implications of these findings.