Transplantation of organs across a species barrier has long been a dream of the transplantation community. Renewed interest in xenotransplantation has emerged due to the short supply of organs available for clinical transplantation. However, transplantation of solid organs across a species barrier has not matched the success of allogeneic combinations, even for closely related species. The rejection response to xenografts is vigorous and not adequately controlled by conventional immunosuppressive agents that control alloreactivity. This may suggest a different mechanism for xenoreactivity, or stronger histocompatibility antigen disparities. This article reviews the current clinical experience with xenografts, mechanisms of xenoreactivity, the induction of tolerance across species disparities, and recent models in which human tissue has been transplanted into other species as an in vivo model of the human immune system.