Caveolae are plasmalemmal invaginations formed by the sequestration of cholesterol and glycosphingolipids with self-associating molecules named caveolins, resulting in a platform for the assembly of signaling complexes at the surface of the cell. The enrichment of the endothelial nitric oxide synthase in caveolae and its direct interaction with caveolin both account for the exquisite regulation of nitric oxide production in cardiovascular tissues. Dissection of the angiogenic signaling cascade downstream vascular endothelial growth factor recently led to recognition that although the former enables the compartmentation of endothelial nitric oxide synthase and optimizes the process leading to its activation, the latter maintains the enzyme in its inactivated state in the absence of stimulation. Alteration in caveolin abundance or subcellular location may lead endothelial cells or cardiac myocytes to favor one mode of regulation over the other and thereby alter the subtle equilibrium governing nitric oxide production in these cells.