The evolutionary history of plant interactions with necrotrophic pathogens that feed on dying host cells and their virulence mechanisms remains fragmentary. We isolated barley Scs6, which is required for the necrotrophic fungus Bipolaris sorokiniana isolate ND90Pr to cause spot blotch disease. Scs6 is located at the Mla resistance locus and encodes an intracellular nucleotide-binding leucine-rich repeat receptor (NLR). In transgenic barley, Scs6 is sufficient to confer susceptibility to ND90Pr in accessions naturally lacking the receptor, resulting in infection-associated host cell death. Expression of Scs6 in evolutionarily distant Nicotiana benthamiana or human embryonic kidney (HEK293) cells reconstitutes a cell death to an uncharacterized non-ribosomal peptide effector produced by ND90Pr-specific non-ribosomal peptide synthetases (NRPSs) encoded at the VHv1 virulence locus, suggesting that the effector directly activates SCS6. Scs6-mediated cell death in HEK293 cells is independent of known vertebrate cell death pathways, but dependent on extracellular calcium. Scs6 is an allelic variant of functionally diversified Mla resistance genes each conferring strain-specific immunity to barley powdery mildew isolates with matching proteinaceous pathogen effectors. Domain swaps between MLA and SCS6 NLRs and expression of the resulting hybrid proteins in N. benthamiana reveal that the SCS6 leucine-rich repeat domain is a specificity determinant for the NRPS-derived effector to activate the receptor. Similarly, four substitutions in an MLA member unresponsive to ND90Pr render the receptor sensitive to the NRPS-derived effector, leading to cell death. Thus, Mla is subject to contrasting evolutionary selection, recognition of biotrophic pathogen effectors and evasion of targeting by a necrotrophic pathogen effector.