The vascular endothelium secretes factors that not only modulate blood vessel tone, but also participate in the development and progression of atherosclerosis through their effects on platelet adhesion and aggregation, thrombogenicity, and cell proliferation. Altered activities of these substances in patients with risk factors for cardiovascular disease (e.g., hypercholesterolemia, hypertension, diabetes, aging, postmenopausal status, smoking, and infections) appear to underlie the atherosclerotic process. There is increasing evidence from both preclinical studies and clinical trials that nitric oxide (NO) plays a pivotal role in the pathophysiology of arteriosclerosis. This review describes the role of NO in human health and disease and summarizes strategies currently being used to measure and improve endothelial dysfunction.