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To review recent advances in the field of endothelial cell heterogeneity, and to apply this knowledge to an understanding of site-specific vasculopathy, including acute lung injury.Published research and review articles in the English language related to endothelial cell biology and endothelial cell heterogeneity.The results of published studies have been used to provide a perspective of endothelial cell phenotypes in health and disease.The structure and function of endothelial cells are differentially regulated in space and time. Far from being a giant monopoly of homogeneous cells, the endothelium represents a consortium of smaller enterprises of cells located within blood vessels of different tissues. Although united in certain functions, each enterprise is uniquely adapted to meet the demands of the underlying tissue. The endothelium may also vary in its response to pathophysiologic stimuli and therefore contribute to the focal nature of vasculopathic disease states. In acute lung injury, the unique properties of the endothelium may conspire with systemic imbalances to localize pathology to the pulmonary vasculature.