Until recently, research on transplantation rejection and tolerance has been directed toward deciphering the mechanisms of the adaptive immune system. However, the emergence that the innate immune system, the body's first-line defense against pathogens, has a strong influence on adaptive immunity has galvanized interest in elucidating the interplay between these two arms of the immune system. The discovery of Toll-like receptors and the characterization of the cellular mediators involved in innate immunity have provided growing evidence that innate immunity affects the adaptive immune response. Emerging evidence has also shown that early “danger signals”'associated with ischemia-reperfusion injury or brain death contribute to innate immune activation, promoting rejection, and inhibiting tolerance induction. In addition, nonspecific stimuli such as increased donor age or patient disease may also serve to exert a synergistic influence on innate immune activation. Ultimately, controlling the events in innate immune activation may help drive tolerance induction and reduce the rate of rejection.