The endothelium releases factors that control vascular relaxation and contraction, thrombogenesis and fibrinolysis, and platelet activation and inhibition. Maintaining the functional integrity of the endothelium, therefore, is critical for the preservation of blood flow and the prevention of thrombosis. This article reviews the primary endothelium‐dependent substances that promote either relaxation (e.g., nitric oxide, prostacyclin) or contraction (e.g., endothelin) of blood vessels, including their physiology, mechanism of effect, and role in endothelial dysfunction. Risk factors for cardiovascular disease, such as hypertension, hypercholesterolemia, diabetes, vascular aging, and estrogen deficiency, are discussed in terms of their contributions to endothelial dysfunction, which may be the initial step in atherogenesis.