Inhibitors of tumor necrosis factor-α (TNFIs) have revolutionized the treatment for patients with a variety of inflammatory illnesses, including rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, and other inflammatory diseases, and have improved the outcomes and quality of life for such patients. Endemic fungal infections, such as coccidioidomycosis, are observed to occur in persons who are treated with these agents and who live in the Coccidioides-endemic area with similar frequency as persons in the general, healthy public but with an increased likelihood of symptomatic infection and extrapulmonary dissemination. Because the control of coccidioidal infections requires the formation and maintenance of granuloma, it is not unexpected that TNFIs, which inhibit granuloma formation, seem to increase the risk of clinical disease. No guidelines exist to address the prevention and management of disease in patients whose treatment course with TNFIs is complicated by subclinical or clinical coccidioidal infection. Therefore, we reviewed the available medical literature and offer suggestions to the approach and treatment of patients with various forms of coccidioidomycosis before and during therapy with TNFIs.