The first list of fungal ‘priority pathogens’ was released by the World Health Organization in 2022, with a warning that some species are increasingly drug-resistant and becoming more widespread [1]. Indeed, the incidence of fungal infections is rising globally. This is due, in part, to the growing number of immune-suppressed populations that are susceptible to such infections and, in part, due to the high proportion of antifungal treatment failures that result in more than 1.5 million deaths annually [2]. Treatment failures may occur because of poor drug penetrance into infected organs, weakened patient immunity that normally enhances drug efficacy, and fungal drug responses that enable growth in the presence of the drug. The latter include antifungal drug resistance, tolerance, and heteroresistance. Candida albicans is the most prevalent cause of fungal infections in Western hospitals and reports of drug-resistant C. albicans drug isolates are relatively rare [3]; the increase in clinical drug resistance is driven largely by the increased prevalence of non-albicans Candida species that are intrinsically drug-resistant. Nonetheless, the high treatment failure frequency (30–50% mortality) is far more frequent than the prevalence of drug-resistant isolates, and we suggest that heteroresistance and tolerance to antifungals may explain some of this discrepancy.

Fungi are eukaryotes and share conserved metabolic and regulatory pathways with their mammalian hosts, complicating the search for effective antifungal drug targets. In addition, some pathogenic species are intrinsically resistant to at least one of the three clinically available drug classes (azoles, echinocandins, and polyenes). We posit that antifungal drug resistance, heteroresistance, and tolerance contribute to treatment failures and infection recurrence 4, 5, 6••. This review will define antifungal drug resistance, heteroresistance, and tolerance and discuss what we know about intrinsic and acquired drug responses, the molecular mechanisms that drive them, and how we might prevent the emergence of these responses in pathogens.