DM (diabetes mellitus) is a metabolic disorder of either absolute or relative insulin deficiency. Optimized insulin injections remain the mainstay life-sustaining therapy for patients with T1DM (Type I DM) in 2006; however, a small subset of patients with T1DM (approx. 10%) are exquisitely sensitive to insulin and lack counter-regulatory measures, putting them at higher risk of neuroglycopenia. One alternative strategy to injected insulin therapy is pancreatic islet transplantation. Islet transplantation came of age when Paul E. Lacy successfully reversed chemical diabetes in rodent models in 1972. In a landmark study published in 2000, Shapiro et al. [A. M. Shapiro, J. R. Lakey, E. A. Ryan, G. S. Korbutt, E. Toth, G. L. Warnock, N. M. Kneteman and R. V. Rajotte (2000) N. Engl. J. Med. 343, 230-238] reported seven consecutive patients treated with islet transplants under the Edmonton protocol, all of whom maintained insulin independence out to 1 year. Substantial progress has occurred in aspects of pancreas procurement, transportation (using the oxygenated two-layer method) and in islet isolation (with controlled enzymatic perfusion and subsequent digestion in the Ricordi chamber). Clinical protocols to optimize islet survival and function post-transplantation improved dramatically with the introduction of the Edmonton protocol, but it is clear that this approach still has potential limitations. Newer pharmacotherapies and interventions designed to promote islet survival, prevent apoptosis, to promote islet growth and to protect islets in the long run from immunological injury are rapidly approaching clinical trials, and it seems likely that clinical outcomes of islet transplantation will continue to improve at the current exponential pace.