The NADPH oxidase was originally identified as a key component of human innate host defence. In phagocytes, this enzyme complex is activated to produce superoxide anion and other secondarily derived ROS (reactive oxygen species), which promote killing of invading micro-organisms. However, it is now well-established that NADPH oxidase and related enzymes also participate in important cellular processes not directly related to host defence, including signal transduction, cell proliferation and apoptosis. These enzymes are present in essentially every organ system in the body and contribute to a multitude of physiological events. Although essential for human health, excess NADPH-oxidase-generated ROS can promote numerous pathological conditions. Herein, we summarize our current understanding of NADPH oxidases and provide an overview of how they contribute to specific human diseases.