With the advent and widespread use of immunomodulating biologic agents, emerging invasive fungal infections are reported increasingly. To date there is no reliable method to screen patients before starting anti-tumor necrosis factor (TNF) therapy to predict their risk for acquiring fungal infections, partly because most of these infections are de novo infections. Patients should be counseled about avoiding high-risk activities that are associated with the endemic mycosis in their geographic areas. Physicians should keep a high level of suspicion for endemic fungal infections when patients receiving anti-TNF therapy or other biologics present with pulmonary or systemic infections. Rapid diagnosis and initiation of antifungal therapy are of utmost importance.