From an experimental procedure, intestinal transplantation (ITx) has evolved over the last 10 yr into a treatment option for patients suffering from short bowel syndrome and who develop life-threatening complications from total parenteral nutrition (TPN) (e.g. liver dysfunction, line sepsis, shortage of venous access, etc.). One-year survival rates are approximately 70% and thus similar to lung Tx. However, the intestine remains the most challenging abdominal organ to transplant. This is because of the severe immune response (mostly rejection) that is produced, and therefore the need for profound immunosuppression with its attendant complications (sepsis, lymphoma, direct drug toxicity). Unlike other organs, graft loss as a result of acute rejection can occur late after transplantation (more than 1 yr post-transplant). With regard to the actual immunosuppressive regimens, considerable experience in patient management is required to optimize outcome of those complex transplants, which are permanently at risk of rejection and infection. ITx remains an unfinished product, and the application of ITx to patients doing well on TPN warrants further research in the understanding of the rejection process, in the development of less toxic and more efficient immunosuppressive protocols, and in the development of immunomodulatory strategies, to better control rejection and thereby reduce the need for immunosuppression.