Islet transplantation into the portal vein is the current clinical practice. However, it has now been recognized that this implantation site has several characteristics that can hamper islet engraftment and survival, such as low oxygen tension, an active innate immune system, and the provocation of an inflammatory response (IBMIR). These factors result in the loss of many transplanted islets, mainly during the first hours or days after transplantation, which could in part explain the necessity for the transplantation of islets from multiple pancreas donors to cure type 1 diabetes. This increases the burden on the limited pool of donor organs. Therefore, an alternative anatomical site for islet transplantation that offers maximum engraftment, efficacious use of produced insulin, and maximum patient safety is urgently needed. In this review, the experience with alternative sites for islet implantation in clinical and experimental models is discussed. Subcutaneous transplantation guarantees maximum patient safety and has become clinically applicable. Future improvements could be achieved with innovative designs for devices to induce neovascularization and protect the islets from cellular rejection. However, other sites, such as the omentum, offer drainage of produced insulin into the portal vein for direct utilization in the liver. The use of pigs would not only overcome the shortage of transplantable islets, but genetic modification could result in the expression of human genes, such as complement regulatory or "anticoagulation" genes in the islets to overcome some site-specific disadvantages. Eventually, the liver will most likely be replaced by a site that allows long-term survival of islets from a single donor to reverse type 1 diabetes. Copyright © 2008 Cognizant Comm. Corp.