Members of the interferon-induced protein with tetratricopeptide repeats (IFIT) family have important antiviral activities. Most IFIT functions involve disruptive protein–protein interactions, which are mediated by the interaction of their tetratricopeptide repeats (TPRs) with other host factors — they block the initiation of translation in this manner. Recently, it was found that IFITs directly recognize viral RNAs bearing a 5′-triphosphate group (PPP-RNA) and form large multiprotein complexes that promote viral clearance. As many viruses, but not mammals, generate PPP-RNAs, this provides a mechanism by which the host can distinguish between self and non-self RNAs. Abbas et al. have now generated crystal structures of human IFIT5 and of human IFIT5 complexed to PPP-RNA; these structures provide insight into how IFITs recognize viral PPP-RNAs. They show that the TPRs of IFIT5 are arranged in an atypical manner to form a deep, narrow pocket that is lined with positively charged residues. This pocket enables IFIT5 to bind single-stranded PPP-RNAs in a non-sequence-specific manner that requires a 5′-overhang of approximately three nucleotides. However, the pocket is too narrow for double-stranded PPP-RNAs.