The difficulties in managing this potentially horrific disease, with its myriad manifestations, are immense, because host factors dramatically impact outcome. Coccidioidomycosis should warrant great respect among clinicians, because, even with dramatic improvements in therapies, outcomes remain poor. Although there have been outstanding successes with these new therapies, tragic losses after years of immense patient suffering still occur. Coccidioidomycosis is a geographically restricted fungus but is one that inflicts tremendous suffering on affected patients. In addition, because of travel and the influx of susceptible hosts, dramatic increases in patients at risk for infection are seen throughout the southwest United States. The extended-spectrum azoles, such as posaconazole and voriconazole, may prove to be more efficacious in the treatment of coccidioidomycosis than prior agents, including amphotericin B, fluconazole, and itraconazole. Additional resources are needed to conduct randomised, controlled clinical trials for the treatment of this disease.