The introduction of insulin therapy for the management of diabetes mellitus is arguably the greatest milestone in the history of modern medicine. beta-cell replacement therapy is the only treatment that reestablishes and maintains long-term physiological normoglycemia. Until recently, successful clinical outcomes of pancreas transplantation for patients with long-standing diabetes were much superior to that of islet transplantation. Significant advances in islet isolation and purification technology, the development of more specific and less diabetogenic immunosuppressants and the prophylactic administration of antiviral agents have rekindled a worldwide interest in islet transplantation. This chapter will review the rationale of islet transplantation and the development of islet isolation and purification. The challenges facing clinical islet transplantation in the twenty-first century will also be introduced.