The endothelium, by releasing nitric oxide (NO), promotes vasodilation and inhibits inflammation, thrombosis, and vascular smooth muscle cell proliferation. These biological actions of NO make it an important component in the endogenous defense against atherosclerosis and its overt clinical complications. Loss of the functional integrity of the endothelium, as seen commonly in the milieu of cardiovascular risk factors, plays an integral role in all stages of atherosclerosis from lesion initiation to plaque rupture. A number of established techniques can assess endothelial function in human vascular beds. The outcome of endothelial testing has profound prognostic implications and is an independent predictor of atherosclerosis disease progression and cardiovascular event rates. The large clinical benefit of statins and angiotensin-converting enzyme inhibitors in patients with atherosclerosis involves favorable effects of endothelial function. Studies of endothelial function represent a prime example of a successful application of insights derived from vascular biology at the bedside.