Optimal therapy for invasive aspergillosis is unknown, and many clinicians have attempted to utilize a combination antifungal approach to improve outcomes. However, while numerous in vitro studies, animal models, and clinical reports suggest the possibility that combination antifungal therapy might offer improved results, there is no definitive accepted strategy. The currently available antifungals used in various combination approaches have not demonstrated clear improvement over monotherapy. The current classes of drugs targeting the cell wall and cell membrane may need adjunctive agents focused on separate cellular pathways, such as cell stress response or cellular signaling, to maximize efficacy. The calcineurin and the Hsp90 pathways are two such untouched arenas in which targeted manipulation may lead to great advances against aspergillosis.