Organ transplant has become one of the strategies for treatment of malignant disease. The transplant-related complications restricted the further development of organ transplantation; graft rejection is most prominent among these complications, which remains a major cause of morbidity and mortality after organ transplant. Toll like receptors 4 (TLR-4) has been shown as a key molecule in innate immunity and immune tolerance. The role of TLR4 in graft rejection after organ transplant is still unknown. This article will review the role and the mechanism of TLR4 to control APC mature, activate T cells, trigger immune attack to organ graft; therefore bring new insights into the pathophysiology of graft rejection and foster the development of new therapies to control graft rejection after organ transplant.