Islet transplantation is now a therapeutic option for patients with unstable type 1 diabetes mellitus (T1DM) with hypoglycemic unawareness. The benefits of this treatment include improvement in metabolic control with normalization of A1c and prevention of severe hypoglycemia. Insulin independence and improved quality of life can be reproducibly obtained by transplanting adequate islet numbers. Current obstacles to the widespread application of beta-cell replacement therapies include limited islet availability and the need for chronic immunosuppression. The emergence of promising interventions may be of assistance in improving islet recovery and favoring engraftment of smaller islet masses with comparable or better efficacy. In the future, regenerative efforts will contribute to overcoming this limitation as well. Combining these approaches with the development of safe immune interventions to induce self tolerance or to induce the permanent acceptance of transplanted tissues will be necessary to achieve long-term success. The steady progress and promising results of recent clinical trials justifies a great optimism toward the widespread application of beta-cell replacement as a treatment of choice for patients with diabetes.