The endothelium is uniquely positioned at the interface between the blood and the vessel wall. As such, it performs multiple functions: It is involved in the regulation of coagulation, leukocyte adhesion in inflammation, vessel tone, and vascular smooth muscle cell growth, and also acts as a barrier to transvascular flux of liquids and solutes. Far from being a passive participant in these events, it is a dynamic tissue, secreting and modifying vasoactive substances, influencing the behavior of other cell types, and regulating extracellular matrix production and composition. During the past 20 years, the endothelium has been the focus of intense experimental work, resulting in the evolution of a new appreciation of its potential role in vascular disease. This review will concentrate on several areas of endothelial biology in which our knowledge of the molecular mechanisms regulating the function of the endothelium has expanded considerably, permitting new insights into the pathogenesis of vascular disease.