Szocs and colleagues,1 in this issue of Arteriosclerosis, Thrombosis and Vascular Biology , have added to our understanding of the role of NAD(P)H oxidase and reactive oxygen species in vascular injury. The study was undertaken by using the rat carotid artery balloon injury model, a well-characterized model of neointimal formation. In this model, vascular balloon injury leads to medial smooth muscle cell proliferation and migration across the internal elastic lamina to form the neointima.2,3 Adventitial myofibroblasts may also migrate across the media and into the neointima within the first week after balloon injury.4 The processes of proliferation and migration of smooth muscle cells and fibroblasts in vitro are critically dependent on the production of reactive oxygen species.5–8 Moreover, several reports suggest that vascular production of reactive oxygen species increases rapidly after balloon injury, and that treatment with nonspecific antioxidant regimens can inhibit experimental neointimal formation.9–14 Although the relevance of the rat balloon injury model to human post-angioplasty restenosis is questionable,15 the well-defined kinetics of neointimal formation in this model provide a unique opportunity to explore the cellular and enzymatic sources of reactive oxygen species during vascular cell proliferation and migration in response to injury in vivo. See page 21 Recent studies indicate that nonphagocytic NAD(P)H oxidases are major sources of reactive oxygen species in the vascular wall. Like the phagocytic respiratory burst NADPH oxidase, non-phagocytic NAD(P)H oxidases reduce molecular oxygen to generate superoxide, which is in turn converted to hydrogen peroxide. However, unlike the phagocytic NADPH oxidase, the NAD(P)H oxidases present in blood vessels are constitutively active, producing relatively low levels of reactive oxygen …