Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. It is considered an endemic disease in some areas of the United States, but it can also be found in other continents. The spores of the fungus are inhaled by patients, and the number of spores as well as the immunological status of the individuals will determine the severity and clinical significance of the infection. Oral lesions are well known and are more common among immunosuppressed patients. They usually present painful, indurated ulcers that can be solitary or multiple, and may strongly simulate oral cancer. Microscopically, a diffuse lymphohistiocytic infiltrate is observed with the presence of epithelioid macrophages that may be organized as well or ill-formed granulomas. Microorganisms are round, small, 2–4-μm-sized structures usually found in the cytoplasm of macrophages or multinucleated giant cells, but also in the stromal compartment, and their amount varies from case to case. Special histological stains like Grocott-Gomori silver reaction and Periodic Acid-Schiff stain are positive for fungi and aid in establishing the correct diagnosis in challenging cases. Systemic antifungal drugs like amphotericin and itraconazole are the treatment of choice for these patients, and prognosis is variable.