Toll-like receptor 4 (TLR4) signals via two distinct pathways — one engages the adaptor protein MYD88 and the other is driven by TRIF. The MYD88 pathway is associated with the induction of pro-inflammatory gene expression, whereas the TRIF pathway is considered to be less inflammatory and more efficient at supporting adaptive immune responses. As such, there is interest in using TRIF-biased TLR4 agonists for vaccine purposes, as they are likely to be less toxic. Previous studies suggested that structural differences in TLR4 ligands may lead to the preferential activation of the TRIF pathway. However, Kolb et al. found that all of the TLR4 agonists that they tested were biased towards TRIF signalling, with these agonists activating the TRIF pathway at lower concentrations than were necessary for MYD88 activation. Notably, this TRIF bias was driven by type I interferons (IFNs), as equivalent concentrations of TLR4 agonists were necessary to recruit MYD88 and TRIF when IFN-mediated signalling was blocked.