Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species (ROS) and are expressed in at least three different homologues in the vasculature. The enzymes consist of a membrane complex of one of the large catalytically active Nox proteins and p22phox and different cytosolic subunits. Reactive oxygen species formation by the nicotinamide adenine dinucleotide phosphate oxidases Nox1 and Nox2 in arteries is a consequence of an activation of the enzymes by different stimuli such as growth factors, cytokines, and cardiovascular risk factors (cigarette smoke, high blood pressure, oxidized lipids). Nox4, in contrast, is constitutively active, and therefore, ROS formation by this enzyme is controlled on the expression level of the protein. The negative vascular effects of ROS, such as endothelial dysfunction, vascular hypertrophy, aneurysm formation, and inflammatory activation, appear to be the consequence of an activation of Nox1 and Nox2. Nox4, in contrast, potentially elicits positive effects because it promotes differentiation and reduces proliferation of cells. Consequently, selective pharmacologic inhibition of Nox proteins has a potential to interfere with cardiovascular disease initiation and progression.