Today small-bowel transplantation is an accepted alternative to total parenteral nutrition (TPN) for treatment of chronic intestinal failure. It has become a life-saving procedure for those patients who cannot be maintained on TPN. Although the first clinical successes were achieved after the introduction of cyclosporine in the 1980s and tacrolimus in the 1990s, many aspects of this process are still incompletely understood, with immunological manifestations remaining particularly complex. The problems after small-bowel transplantation remain the requirement of potent immunosuppression to prevent rejection, as well as infectious problems secondary to the resulting immunoincompetence and loss of barrier function in cases of rejection. However, significant progress has occurred in the last 3 years. In this article we review the background of small-bowel transplantation procedures, present recent results, and discuss future directions in immunosuppression.