Powdery mildew, caused by the biotrophic fungal pathogen Blumeria graminis f. sp. Tritici (Bgt), is one of the most destructive diseases that pose a great threat to wheat production. The wild relatives and progenitors of wheat represent a rich source of powdery mildew resistance. Here, we report the map-based cloning of powdery mildew resistance gene Pm57 from Aegilops searsii. It encodes a tandem kinase protein (TKP) with putative kinase-pseudokinase domains, designated WHEAT TANDEM KINASE 6 (WTK6). The resistance function of Pm57 was validated by transgenic assay, independent mutants, and allelic association analyses. Stable Pm57 transgenic wheat lines showed high levels and all-stage of resistance against diverse isolates of the Bgt fungus and no adverse phenotype, highlighting the utility of Pm57 for deployment as part of a polygenic stack to maximize the durability of powdery mildew resistance.