Vascular diseases are the most common causes of morbidity and mortality in the Western world. These conditions, whether they involve small and/or large vessels, invariably manifest as localized lesions within the vascular tree. For example, atherosclerosis preferentially affects arteries at branch points, the outer wall of bifurcations, and the inner walls of curvatures. An important question is how systemic alterations in blood-borne factors (eg, those associated with cardiac risk factors) result in focal vasculopathy. A clue to the answer lies in the complex spatial and temporal dynamics of the endothelium. The goal of this review is to highlight concepts of endothelial cell heterogeneity and to apply these principles to an understanding of the pathogenesis, diagnosis, and treatment of atherosclerosis.