Over the past two decades, the multiple evidences of plant genes required for pathogen infection have opened new opportunities to improve immunity in crops providing alternative sources of resistance for designing original epidemic control strategies. These genes, the so-called susceptibility (S) genes, are involved in a wide range of plant fundamental processes that are hijacked by the pathogen through the delivery of pathogen effectors. In the wheat - F. graminearum pathosystem, the role of such S genes in the interaction outcome has already been demonstrated in several studies but the identification of their diversity and the characterization of their precise contribution to the disease development remain a major challenge. Improving our knowledge of effectors and of their targets is therefore a particularly promising lever for tracing original S genes. In this framework, we designed original dual-omics approaches to decipher the intricate interplay of F. graminearum effectors with wheat responses during the early stages of the infection progress. Taking advantage of strains of contrasting aggressiveness facing wheat cultivars of different susceptibility, we profiled fungal genes coding for secreted proteins and exhibiting significant expression changes along the infection progress to refine the secretome gene sets and to identify further the most reliable effector’s gene candidates. This approach shed light on a highly conserved and complex infection program based on a core-effectome sequentially expressed during the infection progress. Among the predicted sub-cellular localization of these putative effectors, the plant cell nucleus emerged as a central target and was further validated using heterologous expression in tobacco leaves. The dual-integration of wheat’s responses with the expression data of the F. graminearum core-effector genes led to the identification of putative susceptibility factors mostly involved in the inhibition of plant defense mechanisms of which, several genes corresponded to highly connected master regulators orchestrating wheat responses to FHB. Taken together, our results lead to the identification of reliable key fungal genes involved in the wheat susceptibility to Fusarium graminearum and brought valuable information for further researches to identify their targets.