Cross-species transplantation (xenotransplantation) offers the prospect of an unlimited supply of organs and cells for clinical transplantation, thus resolving the critical shortage of human tissues that currently prohibits a majority of patients on the waiting list from receiving transplants. Between the 17th and 20th centuries, blood was transfused from various animal species into patients with a variety of pathological conditions. Skin grafts were carried out in the 19th century from a variety of animals, with frogs being the most popular. In the 1920s, Voronoff advocated the transplantation of slices of chimpanzee testis into aged men whose “zest for life” was deteriorating, believing that the hormones produced by the testis would rejuvenate his patients. Following the pioneering surgical work of Carrel, who developed the technique of blood vessel anastomosis, numerous attempts at nonhuman primate organ transplantation in patients were carried out in the 20th century. In 1963–1964, when human organs were not available and chronic dialysis was not yet in use, Reemtsma transplanted chimpanzee kidneys into 13 patients, one of whom returned to work for almost 9 months before suddenly dying from what was believed to be an electrolyte disturbance. The first heart transplant in a human ever performed was by Hardy in 1964, using a chimpanzee heart, but the patient died within 2 hours. Starzl carried out the first chimpanzee-to-human liver transplantation in 1966; in 1992, he obtained patient survival for 70 days following a baboon liver transplant. With the advent of genetic engineering and cloning technologies, pigs are currently available with a number of different manipulations that protect their tissues from the human immune response, resulting in increasing pig graft survival in nonhuman primate models. Genetically modified pigs offer hope of a limitless supply of organs and cells for those in need of a transplant.