Although this sorting adaptor had only been implicated in signaling from the cell surface TLR2 and TLR4, Bonham et al. (43) present evidence that MAL/TIRAP is required for resident endosomal TLRs such as TLR9, at least in response to natural viral infection rather than synthetic ligands such as phosphorothioate CpG-containing oligonucleotides. This evidence concerns the gene TLR4 and viral infectious disease.