Endothelial cells respond to injury with acute alterations in mediator generation and surface molecule expression. Endothelial cells may respond, depending on the stimulus, by altering the expression of various genes whose products are central to endothelial cell matrix remodeling, coagulation, and fibrinolysis, as well as interactions with polymorphonuclear leukocytes, platelets, and lymphocytes and in angiogenesis. These responses comprise endothelial activation or differentiation. The molecular events involved in endothelial perception of injury and in regulation of gene expression by cytokines, reactive oxygen intermediates, and mechanical forces are discussed. In addition, because endothelial cells from different sites exhibit heterogeneity regarding their injury responses, where possible this heterogencity in endothelial gene expression is highlighted.