From the late 1950’s, extending for two decades thereafter, amphotericin B was the only broad spectrum antifungal drug which could be systemically administered. Because it was the only option, and because systemic mycoses were relatively infrequent, there was little interest in understanding the mechanism of action of amphotericin B, or expanding options for antifungal therapy. The advent of AIDS and our increasing use of broad spectrum antibacterials, immunosuppressive agents, and prosthetic devices have all acted to create large niches which have been vigorously exploited by fungal pathogens. Consequently the past decade has seen unparalleled increases in opportunistic mycoses, and belatedly in efforts to combat them. The advent of new antifungal drugs has been followed by the appreciation of the limitations of each agent, including those imposed by toxicity, pharmacokinetics, and development of resistance on the part of some fungal pathogens. From amphotericin B we have expanded to multiple new classes of drugs, with multiple alternatives within those classes. However, we have still not reached the optimal agents which are fungicidal, minimally toxic, and can be administered either orally or parenterally. The coming years will see additional classes of drugs introduced as we try to identify this ideal antifungal agent. The following in part documents our present understanding of antifungal drug actions and the mechanism by which some fungi can thwart them. The mycoses contrast dramatically with other microbial pathogens, in which elegant molecular biological techniques have been used to probe resistance mechanisms. This is in part because the fungi have been among the last of the major pathogens to achieve an important role in modern medicine. One example of our tardiness is the very slow development of susceptibility testing, and the only recently seen correlations between in vitro results and clinical outcome.1 Only in the last year has come agreement on a method for testing antifungal azole susceptibility, and this applies only to some yeasts.2,3 Considerable gaps yet require filling.