Bluetongue virus (BTV) is responsible for a disease that affects wild and domestic ruminants. It transmitted by blood-feeding midges of the genus Culicoides. BTV is remarkably variable in its host range and clinical manifestations. This variability is due to several factors related both to the infected host and the viral serotypes and strains. Despite the fact that BTV has been used studied extensively as a model to study the orbiviruses, we still have little understanding of the molecular determinants of BTV virulence. We took advantage of functional proteomic approaches such as high-throughput yeast two-hybrid (Y2H) to map interactions between BTV and cellular proteins. All viral proteins encoded by two serotypes of BTV (BTV8 and 27) were used as baits to screen two cDNA libraries originating from hosts naturally infected by BTV: cattle and Culicoides. Therefore, 56 Y2H screens were performed allowing us to identify a hundred of new cellular interactors. A preliminary global analysis has uncovered many signal transduction factors involved in the modulation of autophagy (BECN1, GABARAPL), apoptosis (AATF, PAWR, CASP8AP2) and the ubiquitin-proteasome system (UBA7, UBE2I, UBA1). The most interesting cellular interactors are currently re-tested by Y2H and N2H (Nanoluciferase two-hybrid) with the viral proteins encoded by BTV8 and 27 but also other serotypes (BTV1, 4, 25 and 30). Specific interactions of a particular virus or group of viruses would shed light on the molecular mechanisms responsible for its virulence/pathogenicity and transgression of cross-species barriers. We have also identified Wilms' tumor 1-associated protein (WTAP) as a new interactor of the BTV-NS4. In contrast to BTV8, 1, 4 and 25, NS4 proteins from BTV27 and BTV30 are unable to interact with WTAP. This interaction with WTAP is carried by a peptide of 34 amino acids (NS422-55) within its putative coil-coiled structure. Most importantly, we showed that binding to WTAP is restored with a chimeric protein where BTV27-NS4 is substituted by BTV8-NS4 in the region encompassing residue 22 to 55. We also demonstrated that WTAP silencing reduces viral titers and the expression of viral proteins, suggesting that BTV-NS4 targets a cellular function of WTAP to increase its viral replication.