Tumour necrosis factor (TNF)-alpha inhibitors are widely used agents in the treatment of a variety of inflammatory and granulomatous diseases. It has long been appreciated that these agents confer an increased risk of tuberculosis; however, more recently it has been recognized that patients being treated with TNFalpha inhibitors are also at significant risk for infection with the endemic fungi, in particular Histoplasma capsulatum, and when infected, to develop severe disseminated infection. Patients often present in an atypical manner and the symptoms of the fungal infection can be mistaken for those of the underlying disease. Thus, delay in diagnosis and treatment is common, and mortality has been high. In an attempt to increase awareness of this problem, the US FDA issued a 'black box' warning for clinicians in September 2008 to alert providers of the risks of endemic fungal infections in patients treated with TNFalpha inhibitors. The management of patients who develop endemic fungal infection while receiving TNFalpha inhibitor therapy should include discontinuation of the TNFalpha inhibitor and early use of antifungal agents including polyenes and/or azoles according to the Infectious Diseases Society of America guidelines for treatment of these infections in immunocompromised hosts.