The relentless increase of invasive fungal infections and poor outcomes associated with available antifungal agents prompted the search for better therapeutic strategies. Combining antifungal drugs was recommended as a means to enhance efficacy in a variety of invasive infections including cryptococcosis, candidiasis, and aspergillosis. With the exception of cryptococcal meningitis, data from controlled clinical trials supporting such combinations are sparse. Moreover, little consensus exists regarding which combinations are synergistic or antagonistic in vitro and in vivo. Based on available data, several principles underlie these combinations.