Candida albicans and Aspergillus fumigatus occur ubiquitously in nature; C. albicans is part of the natural flora of most healthy individuals, and A. fumigatus is commonly found in soil, plant debris, and indoor air. Neither fungus poses a threat to healthy individuals, but each can cause fatal infections in immunocompromised patients. The use of tumor necrosis factor (TNF) antagonists for the treatment of rheumatoid arthritis and other autoimmune diseases has been associated with an increased incidence of opportunistic infections, including infections with both of these fungi. Because the use of TNF antagonists is expected to increase in the future, understanding the role that TNF plays and the effect of its antagonism on host defense against infections with these fungi is critical for reducing the associated morbidity and mortality.