In humans, the first line of defense against viral replication is the IFN antiviral system. When a virus infects a cell, its genome begins to replicate to produce chemically distinct forms of virus RNA such as 5’-triphosphates and double-stranded RNAs. The RIG-I Like Receptors (RLRs) – RIG-I, MDA5, and LGP2 - share conserved DECH-box RNA helicase domains and a regulatory domain that participates in the recognition of foreign RNA species. Additionally, MDA5 and RIG-I contain caspase activation and recruitment domains (CARD), signal transduction motifs that are activated by RNA binding in regulatory domain to initiate the production of IFN. LGP2 does not contain the CARDs and its role in the innate immunity remains to be well understood. The importance of these proteins in the IFN antiviral system is highlighted by the discovery of virus-encoded immune evasion strategies that inhibit the production and signaling of IFN. One such IFN antagonist is the paramyxovirus V-protein. The crystal structure of the carboxyl terminal domain (CTD) V-protein shows a conserved cysteine-rich region along with a highly conserved histidine that coordinates with two zinc atoms to form a zinc-binding domain. This is considered the hallmark of the V-protein. Furthermore, the V-protein is reported to inhibit MDA5-mediated IFN- b synthesis. Unlike MDA5 and LGP2, RIG-I does not interact with the V-protein, indicative of a highly selective interaction. Identification of the MDA5 target site also led to the discovery that LGP2 is bound by the V-protein in the analogous 130 amino acid domain known as the minimal V-protein-binding region (MVBR). To determine the molecular basis for selective RLR targeting, site directed mutagenesis was performed to investigate the MDA5 and LGP2 amino acids required for specific recognition by the V protein. Based on a multiple sequence alignment of the RLRs, a set of mutants designed to target all residues that are the same in MDA5 and LGP2 but different in RIG-I were constructed. The mutant RLR proteins were tested for interaction with and interference by the measles virus V protein. A subset of mutants were identified that fail to be antagonized by the measles virus V protein, resulting in MDA5 and LGP2 proteins that are insensitive to paramyxovirus evasion. These results describe the first MDA5 and LGP2 mutants that are not susceptible to paramyxovirus antagonism.