Toll-like receptors (TLRs) are a family of transmembrane proteins that have a major role in pathogen-induced inflammation and orchestrating an organism's defense against infection. Data are emerging that the TLRs play an important role as a first response to tissue injury linking the innate with the adaptive immune system. The recognition that TLRs are expressed on nonimmune cells including renal and liver cells, and that endogenous, cell-derived ligands (damage-associated molecular patterns) can signal through specific TLRs has expanded the understanding of how these receptors impact a variety of diseases. This review focuses on recent findings elucidating the ability of TLRs to affect transplant outcomes. Specifically, observations demonstrating the link between endogenous TLR ligands and IR injury, how this can affect alloimmunity and transplant tolerance, and therapeutic implications will be discussed.