The growing occurrence of invasive fungal infections and the mounting rates of drug resistance constitute a significant menace to human health. Antifungal drug combinations have garnered substantial interest for their potential to improve therapeutic efficacy, reduce drug doses, reverse, or ameliorate drug resistance. A thorough understanding of the molecular mechanisms underlying antifungal drug resistance and drug combination is key to developing new drug combinations. Here we discuss the mechanisms of antifungal drug resistance and elucidate how to discover potent drug combinations to surmount resistance. We also examine the challenges encountered in developing such combinations and discuss prospects, including advanced drug delivery strategies.