Atherosclerosis, a chronic systemic disease of the vasculature with an inflammatory component, is the primary cause of cardiovascular morbidity and mortality in industrialized countries. Impairment of vascular endothelial cell function in atherosclerosis and in conditions associated with increased cardiovascular risk are important determinants of disease progression. Reduced endothelium-dependent relaxation in the coronary and systemic circulation due to decreased bioavailability of nitric oxide (NO) and increased release of oxygen-derived free radicals promotes the adhesion of leukocytes, thrombosis, inflammation, cell proliferation, and increases in vascular tone. In addition to decreases in bioactive NO, enhanced production of the 21-amino acid peptide endothelin-1 contributes to the progression of atherosclerosis. This paper discusses mechanisms and therapeutic approaches to improving endothelial pathways in atherosclerosis. Restoration of endothelium-derived NO bioactivity through inhibition of the renin-angiotensin system, the endothelin system, or statin therapy improves vascular function in experimental hypercholesterolemia, hypertension and heart failure. These treatments may also have therapeutic benefit for patients at risk or with overt atherosclerosis, and are likely to reduce vascular and myocardial complications of this disease.