In this study, our investigation directed towards the identification of factors required for recognition of MDA5 for viral mRNA revealed that the RNA helicase, DHX29 functions as a dsRNA co-sensor and exclusively interacts with MDA5 for enhanced RNA recognition in response to high molecular weight polyinosinic-polycytidylic acid [HMW-Poly(I:C)] treatment or EMCV infection in immune cells. In this respect, it is worth-mentioning that RNA helicases play critical roles in multiple biological processes, including protein translation initiation and stress granule formation [25–27]. In addition to the potential involvement in innate immune recognition and antiviral immunity [28, 29], several RNA helicases have also been identified as key factors in protein translation initiation [25, 30]. Recently, the RNA helicase DHX29 has been reported to be required for the formation and scanning of 43S translation initiation complexes on mRNAs with 5´-structured untranslated regions (UTRs) [31–33]. More importantly, mRNAs with internal ribosomal entry sites (IRES) occur in many Picornaviridae family viruses, including EMCV, and require DHX29 during translation initiation [34, 35]. Despite the important role of DHX29 in translation initiation of mRNAs with 5´ structured UTRs, particularly those from picornaviruses, its’ role in innate immune response to virus remains largely unknown. Interestingly, our mechanistic studies identify a previously unrecognized role of DHX29 in MDA5-mediated EMCV-specific type I IFN signaling and provide insights on the molecular mechanism by which DHX29 recognizes dsRNA and specifically interacts with MDA5 to render enhanced antiviral immunity.