The fungal pathogen Rhizoctonia solani causes banded leaf and sheath blight (BLSB) in maize (Zea mays) and sheath blight (ShB) in rice (Oryza sativa). R. solani has a wide range of host and severely threatens crop production. The lack of resistant resources against BLSB and the poor understanding of disease resistance mechanism hamper the development of effective approaches to control this fungal disease. Recently, Chinese scientists have made a breakthrough discovery that an F-box protein ZmFBL41 mediates the proteasomal degradation of cinnamyl-alcohol dehydrogenase ZmCAD to regulate BLSB and ShB disease resistance. By genome-wide association analysis, GRMZM2G 109140 (ZmFBL41) was identified as a major QTL candidate gene associated with BLSB disease resistance. ZmFBL41 protein is a member of SKP1-Cullin-F-box (SCF) E3 ubiquitin ligase complex which mediates the degradation of ZmCAD, thus reducing the accumulation of lignin and rendering maize more susceptible to R. solani. Interestingly, in the maize inbred line Chang7-2, the natural variation on two amino acids in ZmFBL41 ^Chang7-2 results in resistance against BLSB. Mechanistically, ZmFBL41 ^Chang7-2 fails to interact with and degrade its substrate ZmCAD, leading to the accumulation of lignin, which consequently enhances maize resistance. This study not only discovers a novel molecular mechanism underlying disease resistance of maize against R. solani, but also provides important theoretical basis and genetic resources for breeding maize and other crops with improved disease resistance.