AbstractGray leaf spot (GLS), caused by the fungal pathogens Cercospora zeae-maydis and Cercospora zeina, is a major foliar disease of maize worldwide (Zea mays L.). Here we demonstrate that ZmWAKL encoding cell-wall-associated receptor kinase-like protein is the causative gene at the major quantitative disease resistance locus against GLS. The ZmWAKL^Y protein, encoded by the resistance allele, can self-associate and interact with a leucine-rich repeat immune-related kinase ZmWIK on the plasma membrane. The ZmWAKL^Y/ZmWIK receptor complex interacts with and phosphorylates the receptor-like cytoplasmic kinase (RLCK) ZmBLK1, which in turn phosphorylates its downstream NADPH oxidase ZmRBOH4. Upon pathogen infection, ZmWAKL^Y phosphorylation activity is transiently increased, initiating immune signaling from ZmWAKL^Y, ZmWIK, ZmBLK1 to ZmRBOH4, ultimately triggering a reactive oxygen species burst. Our study thus uncovers the role of the maize ZmWAKL–ZmWIK–ZmBLK1–ZmRBOH4 receptor/signaling/executor module in perceiving the pathogen invasion, transducing immune signals, activating defense responses and conferring increased resistance to GLS.