Fungal infections are a global concern and the evolution of intrinsic resistance to current antifungals presents an alarming problem. For Cryptococcus neoformans, a human fungal pathogen of primarily immunocompromised individuals, resistance toward treatment strategies demands alternative approaches. Given the prevalence of virulence factor production during cryptococcal infection, an emerging and important field of research encompasses the development of novel antivirulence therapies proposed to improve host immune responses and promote fungal clearance. To accomplish this task, information regarding the presence and role of virulence factors, the mechanisms of action within the host, and the ability to influence fungal susceptibility to antifungals is pertinent. Research into mechanisms of antifungal resistance for C. neoformans is limited but extrapolation from successful studies in other fungal species can improve our understanding of mechanisms employed by C. neoformans and suggest targeted strategies to enhance our ability to combat the pathogen. In this Review, we highlight antifungal therapy options against Cryptococcus, explore current knowledge of underlying mechanisms promoting resistance, and present new opportunities for novel and effective strategies to overcome fungal infections and reduce, or possibly even reverse, the effects of resistance evolution. Combatting the evolution of antifungal resistance in Cryptococcus neoformans. Three antifungals, including amphotericin B, flucytosine, and fluconazole are commonly used to treat cryptococcal infections; however, development of resistance has been reported for each treatment strategy. Such resistance is attributed to alterations of drug targets, upregulation of multi‐drug transporters, and/or the overexpression of drug target or chromosomal aneuploidy. In this Review, we discuss opportunities to overcome antifungal resistance and reduce selective pressures towards resistance through the use of surveillance data collection, anti‐virulence strategies, and drug‐repurposing approaches.