Steady improvements in islet cell processing technology and immunosuppressive protocols have made pancreatic islet transplantation a clinical reality for the treatment of patients with Type 1 diabetes mellitus (T1DM). Recent trials are showing that improved glycemic metabolic control, prevention of severe hypoglycemia, and better quality of life can be reproducibly achieved after transplantation of allogeneic islets in patients with unstable T1DM. Despite these encouraging results, challenges ahead comprise obtaining adequate islet cells for transplant, enhancing islets engraftment, sustaining beta cell mass and function over time, and defining effective immune interventions, among others. In order to overcome the current hurdles to the widespread application of islet transplantation there is a need for implementation of integrated, sequential therapeutic approaches.