Antifungal resistance is a growing concern in clinical medicine, driven by the increasing incidence of fungal infections and the limited arsenal of effective antifungal drugs. This resistance is achieved by intrinsic mechanisms, such as ineffective drug‑target binding, high efflux pump activity and unique cell wall and membrane composition, as well as acquired mechanisms, including genetic mutations, gene duplication, transposon insertions, aneuploidies and loss of heterozygosity. Antifungal tolerance, characterized by subpopulations of fungal cells that persist and proliferate even at high drug concentrations, complicates treatment. The present review aimed to examine the genetic, physiological and epigenetic factors that contribute to antifungal resistance and tolerance. Understanding these mechanisms may enable the development of novel antifungal therapies and effective diagnostic strategies to combat the increasing threat of resistant fungal infection. Advanced diagnostic tools and combination therapies are key for managing resistant infections and ongoing research into these mechanisms may enhance the ability to mitigate antifungal resistance.