Coccidioidomycosis (CM) is an endemic disease in the western United States, northern Mexico, and Central and South America. The severity of coccidioidal infection is highly variable, with potential factors including comorbidities and the patient’s innate and adaptive immune response. Based on data from a predominantly healthy and mainly Caucasian male survey conducted nearly a century ago, approximately 60% of infections are asymptomatic, with an estimated 40% of people experiencing some respiratory symptoms; with 10% of those diagnosed with CM. Disseminated disease occurs in approximately 1% of cases and can involve the meninges and, potentially, any place in the body. It is not yet fully understood why some people experience severe disease while many people do not; it is understood that the immune response has a major role. Immunomodulators, including dupilumab and interferon-gamma (IFN-γ), have shown promise in treating patients with disseminated infection. This article summarizes the latest genetic and immunologic evidence demonstrating immune dysfunction. Immunomodulators and potential therapeutic strategies based on the above are reviewed.