Fusarium head blight is a prevalent disease of bread wheat (Triticum aestivum L. ), which leads to considerable losses in yield and quality. Quantitative resistance to the causative fungus Fusarium graminearum is yet poorly understood. We integrated transcriptomics and metabolomics data to dissect the molecular response to the fungus and its main virulence factor, the toxin deoxynivalenol in near-isogenic lines segregating for two resistance quantitative trait loci, Fhb1 and Qfhs.ifa-5A. The data sets portrait rearrangements in the primary metabolism and the translational machinery to counter the fungus and the effects of the toxin and highlight distinct changes in the metabolism of glutamate in lines carrying Qfhs.ifa-5A. These observations are possibly due to the activity of two amino acid permeases located in the QTL confidence interval, which may contribute to increased pathogen endurance. Mapping to the highly resolved region of Fhb1 reduced the list of candidates to few genes that are specifically expressed in presence of the QTL and in response to the pathogen, which include a receptor-like protein kinase, a protein kinase, and an E3 ubiquitin-protein ligase. On a genome-scale level the individual subgenomes of hexaploid wheat contribute differentially to defense: Especially the D subgenome exhibited a pronounced response to the pathogen and contributed significantly to the overall defense response.