Fungal infections pose a serious threat to human health, especially to immunocompromised patients.1,2 Fungal infections kill more than 1.5 million people each year.3 Recently, the mortality of fungal infections is on the rise because of the increasing drug resistance to the traditional antifungal agents.4,5 New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangostin resulted in interesting antifungal agents with a novel mode of action. These peptidomimetics mimic the fungicidal action of AMPs by directly disrupting negatively charged fungal cell membranes. Two lead compounds (1 and 2) showed potent antifungal activity against a wide range of fungal pathogens, including drug-resistant C. albicans and Fusarium strains, and low cytotoxicity and hemolytic activity against mammalian cells. Both two compounds can kill fungus rapidly by directly disrupting fungal cell membranes and avoid the development of drug resistance. To our knowledge, membrane-targeting xanthone-based antifungals have not been reported previously. These results demonstrated that compounds 1 and 2 may be promising candidates for treating drug-resistant fungal infections.