Cryptococcus neoformans has become a major opportunistic fungal pathogen worldwide. Successful treatment of invasive disease with this fungus has used amphotericin B, flucytosine and various azoles. However, treatment failures continue to occur for a variety of reasons including direct antifungal drug resistance. Issues and mechanisms for antifungal drug resistance in Cryptococcus neoformans are reviewed. Furthermore, approaches and strategies for prevention and treatment of antifungal drug resistance are identified and these include host immune modulation, dose optimization, prophylaxis/empirical regimens, improved drug delivery systems such as lipid preparations of amphotericin B, surgery, combination antifungal treatments and development of new antifungal agents. Copyright 1999 Harcourt Publishers Ltd.