Invasive fungal infections are major causes of mortality in immunocompromised patients. Despite improved outcomes with new antifungals, there remains a pressing need to further improve outcomes, especially with invasive aspergillosis and other invasive mold infections. Combination antifungal therapy is an attractive option that offers the prospect for improved efficacy, decreased toxicity, reduced likelihood for the emergence of resistance, and shorter courses of therapy. The current available evidence regarding the role of combination antifungal therapy for invasive fungal infections is discussed in this article, including data from in vitro studies, animal models, and human clinical trials to try to clarify this important issue. Randomized, prospective clinical trials are urgently needed, especially for invasive aspergillosis.