Signaling through toll-like receptors (TLRs) is believed to be the critical first step in the activation of antigen presenting cells and the initiation of adaptive immune responses. Of these receptors, TLR-4 particularly recognizes endogenous agonists and may be important for allograft responses. We tested this concept using mice with defective function and structure of TLR-4 as recipients of grafts across major and minor histocompatibility barriers. The kinetics of rejection was the same in mutant mice and wild-type controls. Our results highlight an important difference between alloimmune and conventional immune responses.