A critical element restricting the application of liver transplantation is the shortage of human deceased donor organs. Xenotransplantation using pig organs might be a solution to this shortage. Although the problems that still require resolution include the immunologic barrier, the potential risk of transferring infectious agents with the transplanted organ, and uncertainty about whether the transplanted organ will function satisfactorily in the human environment, recent progress in the genetic manipulation of pigs has led to the prospect that clinical xenografting, at least as a bridge to allotransplantation, may be possible in the foreseeable future. Experience with clinical auxiliary and orthotopic liver xenotransplantation and experimental liver xenotransplantation in nonhuman primate and other large animal models is reviewed, and the remaining immunologic problems are discussed. Evidence suggests that, in patients with hepatic failure, the pig liver may be less susceptible to antibody-mediated injury than other pig organs, such as the heart or kidney. Pig Kupffer cells and other macrophages will recognize and phagocytose primate red blood cells, but this problem should be overcome by pretransplant depletion of macrophages from the organ-source pig. From the evidence currently available, it does not seem unduly optimistic to anticipate that a liver from an α1,3-galactosyltransferase gene-knockout pig would survive at least long enough to function as a successful bridge to allotransplantation. © 2008 AASLD.