Antifungal drugs used to treat serious fungal disease fall primarily into three drug classes. These classes include the azoles, echinocandins, and polyenes. Both azoles and polyenes target the cell membrane while echinocandins specifically target cell-wall synthesis. Amphotericin B is the primary drug in the polyene arsenal and is considered fungicidal, or capable of killing fungi. Remaining drugs are primarily fungistatic, meaning that they function by inhibiting growth and viability to assist the patient's natural immunity in clearing infection. This chapter details drugs' mechanism of action, spectrum of activity, pharmacokinetics, and previously reported adverse events. In addition to drug characteristics and use, detection of resistance is discussed. Significant changes have been made in the interpretation of susceptibility testing results. Previously, break points were provided for all Candida spp., in general, but this has progressed to species-specific break points that are dependent on both the fungal species being tested and the drug under evaluation. In addition to making the break points species specific, the Clinical and Laboratory Standards Institute (CLSI) committee realized that the early break points were likely set too high. Current break points are approximately twofold lower than those previously published. Information regarding detecting resistance and incidence of resistance is discussed in regard to several clinically significant species.