AbstractIntracellular TLRs sense viral and bacterial nucleic acids from a wide variety of pathogens. Previous studies have shown that TLR9 requires processing for signalling. Following proteolysis, a fragment corresponding to the C‐terminal part of TLR9 was shown to bind MyD88 and to induce signalling when cells were stimulated with TLR9 ligands. In this issue of the European Journal of Immunology, a study provides evidence that another proteolytic fragment of TLR9 is generated, different to that described previously, consisting of amino acids 1–723 which mediates inhibition of TLR9 signalling. These results suggest that proteolysis undoubtedly is a key step in TLR9 regulation.