NADPH oxidases belong to a group of enzymes that generate reactive oxygen species (ROS) by electron transfer from NADPH to molecular oxygen. The product of this reaction is the superoxide anion (O2−), which undergoes secondary reactions. O2− inactivates NO to yield peroxynitrite and spontaneously or under catalysis of superoxide dismutases reacts to hydrogen peroxide. NADPH oxidases, therefore, limit vascular NO availability and facilitate reactions involving ROS.1 It is now well understood that endothelial dysfunction is largely a consequence of NADPH oxidase activation, as well as of complex secondary reactions that involve different types of ROS. Peroxynitrite oxidizes the NO synthase cofactor tetrahydrobiopterin and stimulates kinases, which both lead to uncoupling of the endothelial NO synthase. NO and O2− may also affect gene expression, and, in particular, NADPH oxidase–derived hydrogen peroxide has been shown to be important in this respect. In addition to the stress-mediated ROS-stimulated gene expression, hydrogen peroxide transiently or irreversibly oxidizes biological materials and, therefore, has complex effects on signaling that are still incompletely elucidated.1 Although the initial work on NADPH oxidases focused on its role for gene expression and endothelial dysfunction at large, the research of recent years aimed at the identification of specific NADPH oxidase–dependent signaling pathways, the understanding of the role of the enzymes in individual disease entities, the identification of NADPH oxidase inhibitors, and finally the demonstration of a relevance of NADPH oxidases in human cardiovascular diseases. Indeed, it is now known that patients with chronic granulomatous disease, which results from loss-of-function mutations of the NADPH oxidase, have an increased vascular NO availability and reduced vascular levels of footprint markers of ROS formation.2 This important observation provided a direct link between NADPH oxidase and endothelial function in humans. Chronic granulomatous disease, however, is too rare …