For more than two decades, islet transplantation has been pursued as a curative treatment for type 1 diabetes mellitus (T1DM) with little success. It is likely that the failures of the past have involved technical difficulties in harvesting human islets, transplantation of insufficient amounts of islet tissue, the antagonistic effects of immune suppressive drugs, including calcineurin inhibitors and glucocorticoids, graft rejection and recurrent autoimmune disease. More recently, success has been reported in seven out of seven consecutive transplants using approaches that overcome the technical and therapeutic problems of the past. Although this success is noteworthy, issues remain that preclude the general application of islet transplants for treatment of the majority of patients with T1DM. These include the need for chronic immunosuppression and the requirement of large numbers of islets. Efforts are under way, using a variety of immunological, molecular and cellular strategies, to make this promising treatment available to the majority of patients with this disease.