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Toll-like receptors (TLRs) are pathogen recognition receptors that orchestrate the innate immune response and the subsequent adaptive immune response. TLRs can be triggered by exogenous ligands expressed by invading pathogens or by the release of endogenous ligands, such as that occurring through cellular injury during the transplantation process. They are now recognized to play an important role in many facets of transplantation biology, including rejection and tolerance, ischemia/reperfusion injury (IRI), and infections after transplantation. The role of TLRs in liver transplantation is unique with respect to other organ transplants because the portal circulation is a continuous source of TLR2 and TLR4 ligands, and this influences TLR signaling pathways, which have a central role in transplantation immunity. This review provides a critical update on recent data outlining the important role of TLRs in liver transplantation, and there is a particular focus on emerging advances in our understanding of rejection and tolerance, IRI, and infections after transplantation and on the ways in which these events may influence the recurrence of diseases such as hepatitis C infection after liver transplantation. Liver Transpl 20:270-280, 2014. © 2013 AASLD.