Rejection remains a major barrier to organ transplantation. This is particularly true for transplanted intestines. T cells play a critical role in rejection. In order for T cells to mediate rejection they must undergo activation. This process is dependent upon two signals: one resulting from the recognition of foreign antigens from the transplanted organ and another signal commonly referred to as a costimulatory signal. T cells receiving the first signal without the costimulatory signal become unresponsive and often die. Thus, if T cells were allowed to receive the first signal from a transplanted organ while the costimulatory signal was blocked, these T cells might die and rejection might be avoided. Using this strategy several investigators have shown that blocking costimulatory signals at the time of transplantation resulted in the long-term survival of transplanted organs in numerous rodent and preclinical primate models. Two of the major costimulatory pathways are the CD28/B7 pathway and the CD40/CD154 pathway. We compared the effect of blocking these pathways on the rejection of transplanted intestines and hearts in mice. Although blocking either of these costimulatory pathways prevented heart rejection, no effect was seen on rejection of intestines. We have shown that this difference is caused by a subset of T cells characterized by the expression of the CD8 molecule on their surface. Our findings demonstrate that these CD8⁺ cells are uniquely important for the rejection of intestine allografts and that rejection caused by CD8⁺ cells can not be inhibited by blocking either the CD28 or the CD40 pathways. Recently, it has been shown that transplanting bone marrow cells augments the effects of blocking costimulatory pathways. We hypothesize that by combining bone marrow transplantation and costimulatory blockade, the rejection of transplanted intestines by CD8⁺ T cells can be inhibited. If confirmed, this approach may be applied clinically to improve the outcome of transplanted intestines and other organs.