Substantial evidence has indicated that transient reactive oxygen species (ROS) can be produced by receptor-mediated biochemical processes, although ROS including superoxide anion and hydrogen peroxide (H2O2) are thought to be by-products of aerobic respiration damaging effectson DNA, protein, and lipid. ROS generation in cell signaling has been extensively studied in terms of NADPHoxidase (gp91phox) in phagocytic cells. However, after identification of the homologs of gp91phox (Nox1, Nox3-5, Duox1-2) from non-phagocytic cells, the function of the generated ROS has been extended into an understanding of various cellular events, including cell growth, differentiation, apoptosis, and inflammation responses. In this seminar I will present the activation mechanism of NADPH oxidase in response to agonists in atherosclerosis. Moreover, discovery of Nox inhibitors for the development of atherosclerosis drug candidate will be presented.