High yield and quality of wheat (Triticum aestivum L.) is seriously threatened by different types of biotic and abiotic stresses, among which fusarium head blight (FHB; caused by the fungus Fusarium graminearum) has historically been one of the most damaging. The mycotoxin produced by this fungus is harmful for human health and livestock feed and productivity. The objectives of this research were to identify molecular defense mechanisms in the AAC Tenacious (Tenacious) variety, which exhibits very high levels of resistance against FHB, both in terms of incidence and severity. In our study, Tenacious was compared with the highly susceptible variety Wilkin following F. graminearum and mock inoculations. Point inoculation method was used in the infection trials. The whole heads of wheat plants in the trials were harvested at 48 hours post inoculation for RNA sample preparation and sequencing. Our RNA-sequencing data analysis identified a total of 202 genes to be differentially upregulated in the resistant interaction compared to the susceptible one. Further gene ontology analysis revealed prominent representations of several pathways involved in plant immune response including lignin biosynthesis, detoxificaton and defense signaling. Moreover, epi-fluorescence microscopy showed strong deposition of phenolic compounds in the infected areas of lemma and palea of the resistant Tenacious, while kernels remained totally intact, suggesting a prominent role for these parts of the florets in suppressing FHB in Tenacious head. Further experiments are under way to fully unravel effective resistance mechanisms against FHB in Tenacious both at the cellular and transcriptional levels.