Pancreatic islet transplantation offers a minimally invasive approach to restore normoglycemia in type 1 diabetics while avoiding the hypoglycemic complications observed with intensive insulin therapy and the surgical complications associated with pancreas transplantation. Although significant progress has been made in clinical islet transplantation, overall outcomes remain suboptimal since many patients lose insulin independence a few years after transplantation and multiple donors are usually needed to achieve independence. The cause of this progressive loss of function is multifactorial, but mounting evidence suggests that much of the islet loss after transplant is directly related to the intraportal transplant site that is used in clinical islet transplantation. Intravascular infusion of the islets triggers a severe,non-specific inflammatory response (immediate blood-mediated inflammatory reaction, IBMIR) which destroys at least 50% of the islet mass. The engraftment of the surviving islets is further compromised by the relatively hypoxic portal venous environment, and the infused islets are exposed to potentially toxic levels of immunosuppressive agents being absorbed from the gut into the portal circulation. Together, these characteristics contribute to early as well as late loss of islet function after transplantation. The gastrointestinal submucosa is a newly described transplant site that can support islet engraftment while avoiding many of the drawbacks associated with intraportal infusion. In addition, this site is easily accessible via upper endoscopy and the submucosal injection procedure is safe and technically straightforward.