The ability to distinguish foreign nucleic acids from abundant self nucleic acids is essential to protect the host from invading pathogens. Several innate immune surveillance systems have evolved to detect nucleic acids and trigger cellular responses to eliminate foreign invaders. For RNA recognition, these include double stranded (ds)RNA-dependent protein kinase, Toll-like receptor (TLR)3, TLR7, TLR8, retinoic acid-inducible gene (RIG)-I and melanoma differentiation-associated gene 5. In the case of the nucleic-acid-sensing TLRs, endosomal localization is thought to be crucial for providing self versus non-self discrimination. For RNA-sensing in the cytoplasm, RIG-I was recently shown to detect and directly bind to the 5'-end of certain viral RNA genomes, specifically, to a 5'-triphosphate group. Such 5'-triphosphates are generally removed from, or masked on, host RNA species, thereby remaining silent to innate immunity and providing a structural basis for the distinction between self and non-self RNA. The mechanisms by which MDA5 senses RNA are unclear at present but seem to involve the sensing of dsRNA structures.