The urgent need for novel antifungal drugs is underscored by the limited number of antifungal agents in clinical development and the global spread of fungal resistance. This study highlights the potential of organoselenium compounds as a new source of scaffolds with promising antifungal activity against a variety of fungal strains. Analysis of over 300 000 compounds screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antibacterial and antifungal activity identified 233 organoselenium derivatives. A remarkable 33% (77) of these exhibited antifungal activity against two representative strains of and , in contrast to only 2% of the non-selenium-containing organic compounds tested by CO-ADD. Of these compounds that displayed antifungal activity (MIC < 16 μg mL), 87% did not exhibit cytotoxicity against mammalian cell lines or haemolytic properties at similar concentrations, compared to only 35% of the organic 'hits'. A subset of these 69 compounds was further evaluated against three clinically relevant fungal strains that often exhibit resistance to current antifungals (, MDR , and ), and generally retained good activity. Lastly, we compared a handful of matched sulfur and selenium compounds which further highlighted the beneficial impact of this bioisosteric conversion on antifungal activity.