Histoplasma capsulatum is endemic throughout most of the United States with a high prevalence of infections in the Midwest and South. Histoplasmosis is the second most common systemic fungal disease in cats that may be more susceptible than dogs. Infection occurs by inhalation of conidia from the mycelial phase, which subsequently convert to the yeast form. Histoplasma capsulatum is phagocytized and harbored by cells of the mononuclear phagocyte system. Infection may be subclinical or cause clinical pulmonary granulomatous disease or dissemination. Disseminated disease predominantly affects the liver, spleen, gastrointestinal tract, bone and bone marrow, integument, and eyes. Primary gastrointestinal histoplasmosis also occurs. Clinical signs of histoplasmosis often are nonspecific, including chronic wasting, fever, anorexia, respiratory signs, and lameness. Gastrointestinal signs (eg, diarrhea with hematochezia or melena) are common in dogs. The definitive diagnosis is made by identification of the yeast in tissue samples. Itraconazole is the treatment of choice.