Tumor necrosis factor (TNF)-alpha is required for host defenses against a number of pathogenic microbes, including Histoplasma capsulatum. In mice, TNF-alpha is necessary for the generation of a protective immune response to both primary and secondary histoplasmosis. Recent reports indicate that, in humans, treatment with inhibitors of TNF-alpha is associated with disseminated histoplasmosis. Here, I review the mechanisms by which inhibition of TNF-alpha may exacerbate infection with H. capsulatum.