AbstractThe management of intestinal failure has evolved dramatically in the last decade. This evolution has been in equal part due to continued improvements in outcomes of intestinal transplantation and to recognition of the need for multidisciplinary management of the patient with intestinal failure. This has led to establishment of intestinal rehabilitation programs, centered only in some instances at institutions with established intestinal transplant programs. Alongside this, improved management of parenteral nutrition‐associated liver disease is creating a paradigm shift in both intestinal‐failure management and in the evolving indications for intestinal transplantation. Unsolved challenges remain: A persistent mortality on the waiting list, especially for patients awaiting combined liver‐intestine transplant; late graft loss to chronic rejection, especially in isolated intestine transplant; the role of antibody‐mediated rejection; and transplantation in the highly sensitized patient continue to defy satisfactory solution. Notwithstanding these challenges, overall outcomes for patients with intestinal failure are vastly improved today and are approaching those for patients with end‐stage renal and liver disease. This review will focus on a comprehensive approach to the patient with intestinal failure, including an overview of intestinal rehabilitation and transplantation. Transplantation outcomes and transplantation of the patient with liver disease are covered elsewhere. Mt Sinai J Med 79:256–266, 2012. © 2012 Mount Sinai School of Medicine