The NOX family NADPH oxidases deliberately generate reactive oxygen species (ROS) such as superoxide. The human genome contains seven members of the family: NOX1 to NOX5 and DUOX1/DUOX2. These enzymes are membrane-integrated flavocytochromes that transfer electrons from NADPH to molecular oxygen for ROS production. The founder of the family is the phagocyte oxidase, presently known as NOX2, which is dormant in resting cells but produces superoxide, a precursor of microbicidal oxidants, during phagocytosis of invading microbes. The significance of NOX2 is evident from the fact that recurrent and life-threatening infections occur in patients with chronic granulomatous disease (CGD) because of a hereditary defect of the Nox2-encoding gene. The thyroid oxidase DUOX2 is required for thyroid hormone synthesis and its genetic inactivation causes congenital hypothyroidism. Recent studies have revealed that NOX-produced ROS also have various regulatory functions: NOX2 defect causes not only severe infections but also noninfectious granuloma formation, indicating its role in immune system regulation; NOX1 and DUOX2 are highly expressed in gastrointestinal epithelial cells, and their gene variations are associated with inflammatory bowel disease (IBD); and NOX4 is cytoprotective against heart damage.