Despite the reported high survival with total parenteral nutrition (TPN) therapy for patients with intestinal failure, a considerable number of patients do not escape the potential risks of TPN-associated complications, including hepatic failure, vanishing of central venous access and line sepsis. Thus, intestinal, liver-intestinal and multivisceral transplantation have recently emerged to rescue those who can no longer be maintained on TPN. Before this development, and for nearly three decades, small-bowel transplantation was plagued with uncontrolled rejection, graft v. host disease and fatal infection. These barriers stemmed from the large gut lymphoid mass and heavy microbial load contained in the intestinal lumen. The recent improvement in survival after the clinical introduction of tacrolimus with achievement of full enteric nutritional autonomy qualified the procedure by the US Health Care Financing Administration as the standard of care for patients with intestinal and TPN failure. The decision was supported by a decade of clinical experience with cumulative improvement in patient and graft survival. In addition, the introduction of new effective immunoprophylactic agents and novel therapeutic approaches has contributed to a further increase in the therapeutic advantages of the procedure. The present review article outlines the current clinical practice of intestinal transplantation and defines new management strategies with the aim of raising the level of the procedure to be a better alternative therapy for TPN-dependent patients.