Abstract: Uncouplers represented by fluazinam show low toxicity, broad-spectrum, and high-efficiency activity, and exhibit strong virulence against pathogenic fungi, oomycetes, and bacteria. However, pathogens have developed increasingly severe resistance to fungicides due to their frequent and extensive use. Investigating the resistance mechanism of plant pathogens to fungicides will contribute to effective delaying or managing resistance. The analysis method for the resistance mechanism of fungicides is usually based on the target protein, but this does not apply to uncouplers as their antifungal efficacy may not occur through target protein binding in pathogens. It is unable to seek the changed amino acid sites in the resistant mutants, making it extremely difficult for exploring resistance mechanisms to uncouplers. This review focuses on the fluazinam and self-developed fungicide SYP-14288 in China and summarizes the research progress of their mode of action and resistance mechanism. The study could provide reference both for the scientific use of uncouplers in the field and for the disclosure of multidrug resistance mechanism, therefore enriching the research system of fungicide resistance and providing a basis for resistance management in practice.