Coccidioides immitis, the primary pathogenic fungus that causes coccidioidomycosis, is most commonly found in the deserts of the southwestern United States and Central and South America. During the early 1990s, the incidence of coccidioidomycosis in California increased dramatically. Even though most infections are subclinical or self-limited, the outbreak is estimated to have cost more than $66 million in direct medical expenses and time lost from work in Kern County, California, alone. In addition to the financial loss, this pathogen causes serious and life-threatening disseminated infections, especially among the immunosuppressed, including AIDS patients. This article discusses factors that may be responsible for the increased incidence of coccidioidomycosis (e.g., climatic and demographic changes and the clinical problems of coccidioidomycosis in the immunocompromised) and new approaches to therapy and prevention.