The endothelium, lining the inner surface of blood vessels, can be considered as the main local regulator of vascular wall homeostasis. It secretes various factors in response to mechanical and hormonal stimuli, which, in turn, influence smooth muscle cell contractility, vascular structure, blood fluidity, and other cell-to-cell interactions. Within the same species, there are, however, variations in endothelial cell function, depending not only on the vascular bed of origin, but also on the size of the vessel within the same vascular territory. Differences have been observed in phenotype, antigen expression, cell size and growth, secretory function, and G-protein expression. Furthermore, some pathological processes affect endothelial function selectively; that is, some vascular beds are sensitive to atherosclerosis while others are not. Understanding these distinctions is particularly important for a rational approach to the treatment of vascular disorders.