Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase complex in which phagocytes are defective in generating superoxide anion and its metabolites. NADPH oxidase activation leads to activation of sequestered neutrophil proteases that mediate host defense. Invasive aspergillosis and other rarer mold diseases are the leading causes of mortality in CGD, reflecting the key role of the phagocyte NADPH oxidase in host defense against opportunistic fungi. Despite recombinant interferon-gamma prophylaxis, invasive filamentous fungal infections are a persistent problem in CGD. Key principles of management of fungal infections involve early recognition and aggressive treatment and appropriate surgical debridement of localized disease. Because CGD is a disorder of phagocyte stem cells in which the gene defects are well defined, it is a model disease to evaluate immune reconstitution through stem cell transplantation and gene therapy. Recent studies using CGD mice show that defects in tryptophan catabolism may underlie the impaired host defense and pathogenic inflammation in CGD and open the potential for novel therapeutic approaches; however, correlative studies in patients are required.