Blastomycosis is a rare but important fungal infection diagnosed primarily in the south central and midwestern United States but also in the American and Canadian borders of the Great Lakes. Epidemics of infection related to point-source exposure include patients of all ages and both sexes, but endemic cases are usually in young to middle-aged adults, with more men than women reported. Pneumonia is the most common manifestation and the lung is almost always the organ initially infected. The lung manifestations range from illness that mimics acute bacterial pneumonia to chronic, destructive lung disease appearing like tuberculosis or lung cancer. Extrapulmonary disease can occur with or without concomitant lung disease. In descending order, cutaneous, osseous, prostatic, and central nervous system involvements are the most frequent manifestations of extrapulmonary blastomycosis. Amphotericin B is curative, but, because of toxicity, oral azole agents have replaced amphotericin B as therapy for less than overwhelming blastomycosis. Itraconazole is now considered to be the agent of choice with fluconazole, voriconazole, and posaconazole having a role in selected patients. In a patient with life-threatening or central nervous system blastomycosis amphotericin B should be given, at least initially.