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Xenotransplantation has progressed from early heroic experiments on the path to meet the ever increasing demands of tissue and organ transplantation in patients with end-stage organ failure. The pig species is regarded as the most promising donor species. However, due to the evolutionary distance, innovative approaches are to be developed to permit life-supporting function in humans. Transplantation of organs from non-human primates has increased our knowledge on rejection mechanisms and provided opportunities for testing modified immunosuppression of the host and genetic modification of the donor. The development of transgenic animals expressing human complement-regulatory factors, and of animals lacking the target for naturally occurring anti-pig antibodies, has essentially eradicated hyperacute rejection of solid organs. However, there is still a need for tolerable immunosuppression or immune-tolerance regimens to provide broadly available procedures in the clinical setting. Safety concerns especially cross-species transmission of infectious pathogens, in particular of porcine endogenous retrovirus. Many studies have indicated that this is highly unlikely. At present, cell and tissue transplantation of islets of Langerhans to diabetic patients is close to being tested in well-designed clinical trials. Further research is required before other porcine xenografts can offer a broadly available therapeutic option in clinical medicine.