Clinical pancreatic islet transplantation can be considered one of the safest and least invasive transplant procedures. Remarkable progress has occurred in both the technical aspects of islet cell processing and the outcomes of clinical islet transplantation. With >1,500 patients treated since 2000, this therapeutic strategy has moved from a curiosity to a realistic treatment option for selected patients with type 1 diabetes mellitus (that is, those with hypoglycaemia unawareness, severe hypoglycaemic episodes and glycaemic lability). This Review outlines the techniques required for human islet isolation, in vitro culture before the transplant and clinical islet transplantation, and discusses indications, optimization of recipient immunosuppression and management of adjunctive immunomodulatory and anti-inflammatory strategies. The potential risks, long-term outcomes and advances in treatment after the transplant are also discussed to further move this treatment towards becoming a more widely available option for patients with type 1 diabetes mellitus and eventually a potential cure.