Crop diseases reduce wheat yields by ~25% globally and thus pose a major threat to global food security1. Genetic resistance can reduce crop losses in the field and can be selected through the use of molecular markers. However, genetic resistance often breaks down following changes in pathogen virulence, as experienced with the wheat yellow (stripe) rust fungus Puccinia striiformis f. sp. tritici (Pst)2. This highlights the need to (1) identify genes that, alone or in combination, provide broad-spectrum resistance, and (2) increase our understanding of the underlying molecular modes of action. Here we report the isolation and characterization of three major yellow rust resistance genes (Yr7, Yr5 and YrSP) from hexaploid wheat (Triticum aestivum), each having a distinct recognition specificity. We show that Yr5, which remains effective to a broad range of Pst isolates worldwide, is closely related yet distinct from Yr7, whereas YrSP is a truncated version of Yr5 with 99.8% sequence identity. All three Yr genes belong to a complex resistance gene cluster on chromosome 2B encoding nucleotide-binding and leucine-rich repeat proteins (NLRs) with a non-canonical N-terminal zinc-finger BED domain3 that is distinct from those found in non-NLR wheat proteins. We developed diagnostic markers to accelerate haplotype analysis and for marker-assisted selection to expedite the stacking of the non-allelic Yr genes. Our results provide evidence that the BED-NLR gene architecture can provide effective field-based resistance to important fungal diseases such as wheat yellow rust.