Reactive oxygen species (ROS) have long been studied in the context of their direct toxic effects on cells. As a result, ROS have conventionally been thought of as a necessary nuisance to aerobic living. However, in recent years, much work has been done to examine the contribution of ROS to the field of immunity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases were identified as one of the key sources of ROS in immune cells. The NOX2 NADPH oxidase in particular has been assigned multiple roles, functioning as a source of antimicrobial ROS, an activator of many signaling pathways, a participant in chemotaxis, an immune modulator, and a critical player in the initiation of antigen cross-presentation. Furthermore, recent studies have revealed a novel role for the NOX2 NADPH oxidase in the activation of autophagy, a cellular degradative pathway. Here, we examine these functions of NOX2 NADPH oxidase in immunity.