The phagocyte NADPH oxidase is a multi subunit protein complex that generates reactive oxygen species at cell membranes and within phagosomes. It is essential for host defence as evidenced by the severe immunodeficiency syndrome caused by a loss of one of the subunits. This is known as chronic granulomatous disease (CGD). However, the phagocyte NADPH oxidase also has a key role to play in regulating immunity and it is notable that chronic granulomatous disease is also characterised by autoimmune and autoinflammatory manifestations. This is because reactive oxygen species play a role in regulating signalling through their ability to post-translationally modify amino acid residues such as cysteine and methionine. In this review, I will outline the major aspects of innate immunity that are regulated by the phagocyte NADPH oxidase, including control of transcription, autophagy, the inflammasome and type 1 interferon signalling.