Antifungal resistance caused by mutations of the drug target, overexpression of the drug target, and drug efflux by the upregulation of transporters is increasingly common. Recently our understanding of fungal drug resistance has been advanced by the identification of three key transcriptional regulators of resistance: Tac1p, Upc2p, and Mrr1p. The discovery of hyperactive variants of these regulators in resistant clinical isolates confirms the importance of transcriptional regulation in the development of antifungal resistance. Alternative mechanisms of drug resistance including aneuploidy and biofilm formation have recently been documented in fungi; as well as the phenomenon of drug tolerance. Characterization of the transcriptional regulation of fungal drug resistance and the identification of novel mechanisms of resistance has implications for current therapy and for the development of future antifungal drugs.