Although our understanding of the immunological mechanisms of transplant tolerance induction has greatly improved, how the innate immune system impacts transplant tolerance has only been recently appreciated. In this review, the involvement of the innate immune receptors, Toll-like receptors (TLRs), in both experimental models of acute allograft rejection and transplant tolerance induction in addition to clinical studies of organ transplantation are described. Several inflammatory cytokines, including IL-6, TNF-α, and type I interferons, which are induced by TLRs and other activators of innate immunity, prevent transplant tolerance induction. Their induction may be provoked by environmental exposures, such as viral or bacterial infections. Further investigation as to the innate inflammatory basis that controls the balance between immune acceptance and allograft rejection may lead us closer to the elusive goal of transplant tolerance acquisition.