Technical Abstract: Co-application of certain types of compounds with conventional antimicrobial drugs results in the enhancement of efficacy of drugs through a mechanism termed chemosensitization. We show that kojic acid (KA), a natural product, is a potent chemosensitizer to complex III inhibitors of mitochondrial respiratory chain of fungi. KA greatly lowers minimum inhibitory concentrations of complex III inhibitors, such as strobilurins, against filamentous fungi. KA also functions as a chemosensitizer to hydrogen peroxide (H2O2), which mimics reactive oxygen species involved in host defense during infection, against human pathogens or Penicillium strains infecting crops. KA-mediated chemosensitization to H2O2 seemed specific for filamentous fungi, indicating strain- or drug-specificity exists during chemosensitization. KA could serve as a promising chemosensitizer to complex III inhibitors or H2O2 against certain human pathogens or Penicillium species. Interpretive Summary: Effective control of fungal pathogens occurring in agricultural farms or humans (especially immunocompromised patients) is a continuous problem. Development of resistance to available antifungal drugs results in unremitting searches for new antifungal agents or alternative control methods. In this report, we show that kojic acid, a safe, natural compound, can enhance the antifungal activity of certain commercial antimycotic drugs. Discovery of this synergism is based upon pinpointing vulnerable targets in fungi, namely energy production or antioxidation. Results of this study will ultimately lead to prevention of development of fungal resistance to conventional fungicides, such as strobilurins. It will also lead to lowering costs or dosages of commercial drugs or fungicides necessary for effective control of fungal pathogens.