Histoplasmosis is one of the most frequent causes of fungal respiratory infection in endemic regions, has a broad spectrum of clinical manifestations and can present in several forms. The extent of disease is determined by the number of conidia inhaled, the immune response of the host and the integrity of the respiratory tract. From an initial and most benign form, acute pulmonary histoplasmosis (an influenza-like illness that is typically asymptomatic or mild in persons without prior immune compromise), histoplasmosis can become a lifethreatening progressive disseminated infection (PDH) that affects mainly immunocompromised patients, with high morbidity and mortality. Chronic pulmonary histoplasmosis is an uncommon manifestation of Histoplasma infection, with features similar to pulmonary tuberculosis, and if it remains undiagnosed or untreated it also can cause significant morbidity. Some rare but serious complications may also occur that are produced by an excessive immune response, such as mediastinal fibrosis, histoplasmoma and broncholithiasis. Histoplasmosis is highly endemic in regions of North, Central and South America as well as being reported in parts of Asia and Africa. The risk of histoplasmosis is greatest in patients with HIV infection, especially those with CD4+ counts of <200 cells/μL. We review clinical manifestations, radiological findings and treatment options according to the clinical form (induction therapy and maintenance therapy), as well as different diagnosis tools and new laboratory tests that have been recently developed and validated and are becoming widely available. These should have an impact in reducing time for diagnosis and starting therapy and in reducing morbidity and mortality, especially in patients with HIV infection, where histoplasmosis is currently estimated to be responsible for 5-15% of AIDS-related deaths.