Chronic granulomatous disease is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections and disordered inflammation. We propose that NADPH oxidase has a key role in regulating acute neutrophilic and T cell responses, which in turn restrains fungal growth and calibrates the inflammatory response to minimize injury and allergy. In this model, superoxide-induced activation of indoleamine 2,3-dioxygenase (IDO) is a central mechanism by which the optimal balance of antifungal host defense and immune tolerance occurs. This model is based on studies in mice and requires correlation in humans.