The intestine has long been seen as a "forbidden" organ to transplant and even nowadays it remains the most challenging abdominal organ to transplant. Large animal experiments have been pivotal, first in developing reproducible and clinically applicable surgical techniques for transplanting the intestine and second, in revealing the unique physiological, immunological, and microbiological challenge that intestinal transplantation (ITx) represents. More recently, large animal models have been used to test new immunosuppressive drugs (FK 506) that have been then successfully used clinically. ITx is no more an experimental endeavor and survival figures of about 70% can be reached at one year, justifying routine application of ITx to patients who do not tolerate total parenteral nutrition. However, ITx remains in 1999 an "unfinished product" and further research will need to be done to allow wider application of ITx to patients without total parenteral nutrition (TPN) related complications. Further research will focus on the following aspects: (1) refined understanding of the factors accounting for the high immunogenicity of the intestine; (2) development of immunomodulatory strategies to reduce graft immunogenicity and to induce specific hyporesponsiveness; (3) development of new immunosuppressants, and their usage in combination, to act more specifically on the immune response, and at the price of less toxicity; (4) development of surgical alternatives to alleviate the organ shortage: graft size reduction, live related ITx. Importantly these questions will need to be addressed in clinically relevant animal models before they are applied to man.