Toll-like receptor-4 (TLR-4) has been increasingly recognized to play a critical role in the pathogenesis of ischemia-reperfusion injury (IRI) of renal grafts. This review provides a detailed overview of the new understanding of the involvement of TLR-4 in ischemia-reperfusion injury of renal grafts and its clinical significance in renal transplantation. TLR-4 responds not only to exogenous microbial motifs but can also recognise molecules which are released by stressed and necrotic cells, as well as degraded products of endogenous macromolecules. Up-regulation of TLR-4 is found in tubular epithelial cells, vascular endothelial cells and infiltrating leukocytes during renal ischemia-reperfusion injuries, which was induced by massive release of endogenous damage-associated molecular pattern molecules such as HMGB-1. Activation of TLR-4 promotes the release of pro-inflammatory mediators, facilitates leukocyte migration and infiltration, activates the innate and adaptive immune system and potentiates renal fibrosis. TLR-4 inhibition serves as the target of pharmacological agents, which could attenuate ischemia reperfusion injury and associated delayed graft function and allograft rejection. There is evidence in the literature showing that targeting TLR-4 could improve long-term transplantation outcomes. Given the pivotal role of TLR-4 in ischemia reperfusion injury and associated delayed graft function and allograft rejection, inhibition of TLR-4 using pharmacological agents could be beneficial for long-term graft survival.