Medical advances have led to increased numbers of immunocompromised patients living longer. Coinciding with this increase in the immunocompromised patient population is an increase in the number of clinically significant fungal infections. Unfortunately, widespread use of the limited numbers of antifungal agents to treat these infections has led to the development of drug resistance. Thus, in an attempt to sort out the mechanisms of resistance for each of the systemically useful antifungal agents, a comprehensive review of the literature has been carried out. The most common mechanisms for the development of resistance involve changes in the enzymatic pathways which serve as the drug targets. For instance, changes in enzymes responsible for the biosynthesis of ergosterol, the target of azole activity, lead to azole resistance. Another common mechanism used by fungi to avoid drug toxicity includes reduced intracellular accumulation of the drug through both decreased permeability and energy-dependent efflux pumps. Using our current understanding of the mechanisms of drug resistance as a template, several strategies to overcome resistance have been identified. These include improvement of host immune function, the use of adjuvant surgery, the development of new drug delivery systems for currently available drugs and the development of new classes of antifungal agents. Also, clinical trials to establish appropriate drug doses and duration of therapy are needed, as well as the benefits of antifungal prophylaxis explored and the use of combination therapies entertained. The war against drug resistant fungi has been identified as we approach the year 2000. With careful and cogent investigations, we do have the tools to fight back against these opportunists. Of all the strategies reviewed, however, in our opinion, the development of new antifungal drugs is likely to have the most significant future impact on our management of drug resistance in fungal infections.