The treatment of the major systemic fungi encountered in the United States--Histoplasma capsulatum, Blastomyces dermatitides, and Coccidioides immitis--depends on an understanding of the natural history of disease. Clinical manifestations of these infections can range from an asymptomatic disease that requires no therapy to an illness that is incurable and requires long-term suppression with antifungal agents to produce a balanced host-to-parasite relationship. This article discusses the natural history of disease caused by H. capsulatum, B. dermatitides, and C. immitis and various clinical situations that require antifungal chemotherapy.