Pancreatic islet transplantation as a cell-based treatment for diabetes mellitus has been pursued for over quarter of a century, ever since the first successful use of this approach to cure diabetes mellitus in rodents in the 1970s. However, even though autoislet intrahepatic transplantation in patients with chronic pancreatitis who did not have diabetes mellitus was successful in the 1980s, reliable success with alloislet transplantation in patients with diabetes mellitus remained elusive until the year 2000. The reasons for previous failures appear to include use of corticosteroids as an immunosuppressive agent, a drug that both interferes with islet β-cell function and promotes resistance to insulin action. Corticosteroid-free immunosuppressive regimens in one recent series have permitted much greater success for over 1 year. Benefits accrued in this series include normal fasting glucose levels, normal levels of glycosylated haemoglobin, and total independence from exogenous insulin or other therapy for hyperglycaemia. These dramatic results have presented the research community with the challenges of replicating these results and, ultimately, with providing solutions to the serious supply and demand issues that will inevitably follow.