BACKGROUND: Fusarium head blight (FHB) caused by Fusarium graminearum Schwabe is one of the most prevalent diseases of wheat (Triticum aestivum L.) and other small grain cereals. Resistance against the fungus is quantitative and more than 100 quantitative trait loci (QTL) have been described. Two well-validated and highly reproducible QTL, Fhb1 and Qfhs.ifa-5A have been widely investigated, but to date the underlying genes have not been identified. RESULTS: We have investigated a gene co-expression network activated in response to F. graminearum using RNA-seq data from near-isogenic lines, harboring either the resistant or the susceptible allele for Fhb1 and Qfhs.ifa-5A. The network identified pathogen-responsive modules, which were enriched for differentially expressed genes between genotypes or different time points after inoculation with the pathogen. Central gene analysis identified transcripts associated with either QTL within the network. Moreover, we present a detailed gene expression analysis of four gene families (glucanases, NBS-LRR, WRKY transcription factors and UDP-glycosyltransferases), which take prominent roles in the pathogen response. CONCLUSIONS: A combination of a network-driven approach and differential gene expression analysis identified genes and pathways associated with Fhb1 and Qfhs.ifa-5A. We find G-protein coupled receptor kinases and biosynthesis genes for jasmonate and ethylene earlier induced for Fhb1. Similarly, we find genes involved in the biosynthesis and metabolism of riboflavin more abundant for Qfhs.ifa-5A.