Reactive oxygen species (ROS), especially superoxide anion and hydrogen peroxide, are important signaling molecules in cardiovascular cells. ROS participate in growth, apoptosis, and migration of vascular smooth muscle cells, in the modulation of endothelial function, including endothelium-dependent relaxation and expression of proinflammatory phenotype, and in the modification of the extracellular matrix. They have also been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation leading to coronary artery disease (CAD). The NAD(P)H oxidase is a multisubunit enzyme that catalyzes the reduction of molecular oxygen to form superoxide (O2*-). Although first described in phagocytes, NAD(P)H oxidases have also been demonstrated as major sources of superoxide in vascular cells and myocytes. Enhanced superoxide production increases nitric oxide inactivation and leads to an accumulation of peroxynitrites and hydrogen peroxide. An entire new family of NAD(P) H oxidase (Nox) homologs has emerged, which vary widely in cell and tissue distribution as well as in function and regulation. Recent and ongoing research tends to highlight the biochemical characters, activation paradigms, structure, and function of this enzyme. In this review, we provide a brief overview of structural features of NAD(P)H oxidases and then discuss their role in pathophysiology of CAD.