Non-self RNA appearing in a cell as a result of viral replication is detected by a cytoplasmic sensor called RIG-I-like receptor (RLR). RLR consists of RIG-I, MDA5, and LGP2, which are DExD/H helicases. Domain structures of RLR for detecting non-self RNA and for relaying signals downstream have been elucidated. Different viruses produce structurally different RNA species and are sensed differentially by RLR molecules to initiate antiviral responses and subsequent antigen-specific adaptive immunity.