The endothelium modulates vascular tone by producing vasodilator and vasconstrictor substances. Of these, the best characterized and potentially most important are nitric oxide (NO.) and O2-.. These small molecules exhibit opposing effects on vascular tone and chemically react with each other in a fashion that negates their individual effects and leads to the production of potentially toxic substances, such as peroxynitrite (ONOO-). These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis. The precise O2-. source within vascular tissue remains to be determined. Recent work demonstrated that in endothelial cells as well as in vascular smooth muscle cells, a membrane-associated NAD(P)H-dependent oxidase represents the most significant O2-. source. Interestingly, this oxidase is activated upon stimulation with angiotension II, suggesting that under all conditions of an activated circulating and/or local renin-angiotensin system endothelial dysfunction secondary to increased vascular O2-. production is expected.