This article reviews the major role that the vascular endothelium plays in pathophysiological processes related to metabolism, vascular function, and blood coagulation. Normally an antithrombotic surface, inflammation activates endothelium to become a prothrombotic and pro-inflammatory interface that is critically involved in multi-organ failure in patients with severe systemic diseases including sepsis. Improving endothelial functions in sepsis is a major therapeutic challenge.