This review summarizes the clinical history and rationale for xenotransplantation; recent progress in understanding the physiologic, immunologic, and infectious obstacles to the procedure's success; and some of the strategies being pursued to overcome these obstacles. The problems of xenotransplantation are complex, and a combination of approaches is required. The earliest and most striking immunologic obstacle, that of hyperacute rejection, appears to be the closest to being solved. This phenomenon depends on the binding of natural antibody to the vascular endothelium, fixation of complement by that antibody, and finally, activation of the endothelium and initiation of coagulation. Therefore, these three pathways have been targeted as sites for intervention in the process. The mechanisms responsible for the next immunologic barrier, that of delayed xenograft/acute vascular rejection, remain to be fully elucidated. They probably also involve multiple pathways, including antibody and/or immune cell binding and endothelial cell activation. The final immunologic barrier, that of the cellular immune response, involves mechanisms that are similar to those involved in allograft rejection. However, the strength of the cellular immune response to xenografts is so great that it is unlikely to be controlled by the types of nonspecific immunosuppression used routinely to prevent allograft rejection. For this reason, it may be essential to induce specific immunologic unresponsiveness to at least some of the most antigenic xenogeneic molecules.