Histoplasmosis remains a common infection in endemic regions of North America and Latin America, causing a broad spectrum of clinical findings. Experience during recurrent outbreaks in Indianapolis has shown the importance of immunosuppressive conditions including the acquired immunodeficiency syndrome (AIDS) as a risk factor for disseminated disease and expanded our knowledge of the common clinical manifestations. Pericarditis, rheumatologic manifestations, esophageal compression, and sarcoidlike manifestations were found to be relatively common findings in histoplasmosis. These studies have established the useful role of serologic testing and have led to the discovery of antigen testing for diagnosis of histoplasmosis. This experience also has offered the opportunity to examine the outcome of treatment in persons with AIDS, contributing to studies that have found itraconazole to be an excellent alternative to amphotericin B in persons with mild or moderately severe infection.