A few groups have endured the challenges of time, anecdotal success stories, logistic and funding impediments, to bring the field of clinical islet transplantation where it stands today. The recent improvement in clinical results has paralleled a renewed interest in islet transplantation and an increasing number of centers have entered the field. Selected institutions have now clearly demonstrated that insulin independence can be a reproducible and achievable goal. Other centers struggle with mixed results, while occasional early failures of islet transplants are still observed. This center effect underlines not just a learning curve, but also the complexity of the approach, which requires multidisciplinary expertise and attention to critical variables that need to be closely monitored to assure adequate clinical outcomes. The future success and large scale applicability of islet transplantation will rely on the synergistic research progress in critical areas that contribute to the sequential and integrated approach required for success in clinical islet transplantation.