Until very recently, outcomes from small bowel transplantation (SBTx) lagged behind those in liver, heart, and kidney transplantation because of the magnitude of the immunologic burden; the strong expression of histocompatibility antigens; and the contamination in grafts by bacterial organisms. With novel techniques of immune-induction therapies, such as recipient "preconditioning" with lymphocyte reduction, followed by the more subtle use of immunosuppression-based single-agent tacrolimus, graft and host 1-year survival is now over 90% in the most active US centers, a finding that parallels the outcomes in liver and kidney transplantation. In contrast to the alternative therapy for permanent intestinal failure, home total parenteral nutrition (TPN), SBTx improves quality of life and restores digestive and absorptive function, making patients nutritionally autonomous. With survival beyond 1 to 3 years, the procedure is cost-effective. Current results support expansion of the indications for SBTx from use as salvage therapy for patients with TPN failure to preemptive therapy for patients at risk of developing TPN failure.