Genetic and acquired (disease- or therapy- related) host immune factors increase the risk for IFIs. In addition to antifungal drug therapy, modulation of host defenses by the use of HGFs and IFN-gamma has been supported by extensive in vitro and in vivo preclinical data. Clinical studies on the prevention or the adjunctive therapy of IFIs in combination with antifungal agents are limited, however, and do not allow specific recommendations for their cost-effective use in most of the immunodeficient settings. There is an urgent need to push forward with well-structured, randomized clinical trials to determine optimal dose, duration, and timing for different combinations of immunotherapy and antifungal agents in high-risk patients.