Fusarium head blight (FHB), which is mainly caused by Fusarium graminearum, is a destructive wheat disease that threatens global wheat production. Fhb1, a quantitative trait locus discovered in Chinese germplasm, provides the most stable and the largest effect on FHB resistance in wheat. Here we show that TaHRC, a gene that encodes a putative histidine-rich calcium-binding protein, is the key determinant of Fhb1-mediated resistance to FHB. We demonstrate that TaHRC encodes a nuclear protein conferring FHB susceptibility and that a deletion spanning the start codon of this gene results in FHB resistance. Identical sequences of the TaHRC-R allele in diverse accessions indicate that Fhb1 had a single origin, and phylogenetic and haplotype analyses suggest that the TaHRC-R allele most likely originated from a line carrying the Dahongpao haplotype. This discovery opens a new avenue to improve FHB resistance in wheat, and possibly in other cereal crops, by manipulating TaHRC sequence through bioengineering approaches.