There is growing evidence that oxidative stress, meaning an excessive production of reactive oxygen and nitrogen species, underlies many forms of cardiovascular disease. The major source of oxidative stress in the artery wall is an NADPH oxidase. This enzyme complex in vascular cells, including endothelium, differs from that in phagocytic leucocytes in both biochemical structure and functions. The crucial flavin-containing catalytic subunits Nox1 and Nox4 are not present in leucocytes, but are highly expressed in vascular cells and upregulated in vascular remodeling, such as that found in hypertension and atherosclerosis. This offers the opportunity to develop "vascular specific" NADPH oxidase inhibitors that do not compromise the essential physiological signaling and phagocytic function carried out by reactive oxygen and nitrogen molecules. Although many conventional antioxidants fail to significantly affect outcomes in cardiovascular disease, targeted inhibitors of NADPH oxidase that block the source of oxidative stress in the vasculature are more likely to prevent the deterioration of vascular function that leads to stroke and heart attack.