The vascular endothelium, once believed to act solely as a mechanical barrier is, in fact, the body’s most active paracrine organ serving a vital role in vasomotion and thromboresistance. Vasoactive compounds such as prostacyclin and endothelium-derived relaxing factor maintain coronary blood flow in response to physiologic demands, while their antiplatelet effects act along with tissue plasminogen activator and heparin-like species to prevent local thrombus formation. Structural and functional endothelial abnormalities may predispose to vascular thrombosis or impair normal vasodilatory responses to increasing metabolic demands. Acquired endothelial dysfunction following coronary reperfusion, aortocoronary bypass grafting and balloon angioplasty plays a vital role in short- and long-term patient outcome. Future therapies in cardiovascular disease must consider strategies to preserve and facilitate the structural and functional integrity of the vascular endothelium.