Xenotransplantation, i.e. transplantation across species, is increasingly being viewed a potential solution to the problem of severe shortage of transplant donors. Clinical application of xenotransplantation is, however, limited in large part by the pre-eminent hurdle of the immune response of the recipient against the graft. This immunologic reaction is mediated initially by natural xenoreactive antibodies, complement and natural killer cells, and later by elicited humoral and cellular immune responses that ultimately lead to graft failure. Progress in understanding the cellular and molecular basis of xenograft rejection has characterized the past few years. Additional hurdles to xenotransplantation include physiologic incompatibility of the transplant and the risk of infections. The recent development of novel strategies to overcome xenograft rejection has brought about great optimism that xenotransplantation may be attainable in the near future.