Coccidioidomycosis or Valley Fever is a fungal disease that occurs primarily in the southwestern United States. Of the estimated 150,000 U. S. coccidioidomycosis infections per year, approximately 60% occur in Arizona, making this state the focal point for investigation of the disease. In this manuscript, we describe the epidemiology of coccidioidomycosis reported in Arizona over the last decade, hypotheses for the findings, and Arizona's response to the rising epidemic. Coccidioidomycosis surveillance data in Arizona consist of basic demographics of all laboratory and physician-diagnosed cases, the reporting of which has been mandated by law since 1997. The rate of reported coccidioidomycosis has more than quadrupled over the last decade from 21 cases per 100,000 population in 1997 to 91 cases per 100,000 in 2006 (P < 0.001). Case rates in older age groups (>/=65 years old) have more than doubled since 2000 (P < 0.001). These data demonstrate the rising coccidioidomycosis epidemic in Arizona, especially among the elderly. The increase in the numbers of reported cases can be partially explained by the institution of mandatory laboratory reporting in 1997, but the cause of the persistent rise after 1999 is unknown. Further investigation of coccidioidomycosis will not only assist with the development of public health interventions to control this disease in Arizona and the southwestern United States, but will also provide important information to prepare for a bioterrorism event caused by this select agent.