Although histoplasmosis is highly endemic in certain regions of the Americas, disease may be seen globally and should not be overlooked in patients with unexplained pulmonary or systemic illnesses. Most patients exhibit pulmonary signs and symptoms, accompanied by radiographic abnormalities, which often are mistaken for community-acquired pneumonia caused by bacterial or viral agents. Once a diagnosis is considered, a panel of mycologic and non–culture-based assays is adequate to establish a diagnosis in a few days to a week in most patients. Once diagnosed, the treatment is highly effective even in immunocompromised patients.