Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory state, and prothrombic properties. It is associated with most forms of cardiovascular disease, such as hypertension, coronary artery disease, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure. Mechanisms that participate in the reduced vasodilatory responses in endothelial dysfunction include reduced nitric oxide generation, oxidative excess, and reduced production of hyperpolarizing factor. Upregulation of adhesion molecules, generation of chemokines such as macrophage chemoattractant peptide-1, and production of plasminogen activator inhibitor-1 participate in the inflammatory response and contribute to a prothrombic state. Vasoactive peptides such as angiotensin II and endothelin-1; the accumulation of asymmetric dimethylarginine, an endogenous nitric oxide inhibitor; hypercholesterolemia; hyperhomocysteinemia; altered insulin signaling; and hyperglycemia can contribute to these different mechanisms. Detachment and apoptosis of endothelial cells (anoikis) are associated phenomena. Endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Reductions in circulating endothelial progenitor cells that participate in regeneration of the endothelium participate in endothelial pathophysiology. The severity of endothelial dysfunction has been shown to have prognostic value for cardiovascular events. Correction of endothelial dysfunction may be associated with reduced cardiovascular risk. Circulating endothelial progenitor cells may represent a potential therapeutic approach for endothelial dysfunction.