The endothelial lining of blood vessels shows remarkable heterogeneity in structure and function, in time and space, and in health and disease. An understanding of the molecular basis for phenotypic heterogeneity may provide important insights into vascular bed-specific therapies. First, we review the scope of endothelial heterogeneity and discuss its proximate and evolutionary mechanisms. Second, we apply these principles, together with their therapeutic implications, to a representative vascular bed in disease, namely, tumor endothelium.