Intensive glycaemic control reduces the diabetic microvascular disease burden but iatrogenic hypoglycaemia is a major barrier preventing tight glycaemic control because of the limitations of subcutaneous insulin preparations and insulin secretagogues. Problematic hypoglycemia, defined as two or more episodes per year of severe hypoglycemia or as one episode associated with impaired awareness of hypoglycemia, extreme glycemic lability, or major fear and maladaptive behavior, is a challenge, especially for patients with long-standing type 1 diabetes. Severe hypoglycaemia is uncommon early in the disease as robust physiological defences, particularly glucagon and adrenaline release, limit falls in blood glucose whilst associated autonomic symptoms drive patients to take action by ingesting oral carbohydrate. With increasing diabetes duration, glucagon release is progressively impaired and sympatho-adrenal responses are activated at lower glucose levels. Repeated hypoglycaemic episodes contribute to impaired defences, increasing the risk of severe hypoglycaemia in a vicious downward spiral. Current therapies are effective in preventing severe hypoglycemic events (SHEs) in 50-80% of patients with Impaired awareness of hypoglycemia (IAH) and SHEs, leaving a substantial number of patients at risk. For selected individuals with type 1 diabetes, pancreatic islet transplantation (IT) prevents recurrent severe hypoglycemia and optimizes glycemia, although ongoing systemic immunosuppression is needed. In response to insulin-induced hypoglycemia after islet transplantation, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long-standing T1D. Interestingly the long-term maintenance of hypoglycaemia awareness that returns after islet cell/pancreas transplantation in patients with diabetes is not prevented by significant autonomic neuropathy and is better accounted for by other factors such as reversal of hypoglycaemia-associated autonomic failure. In conclusion, about half of patients presenting with problematic hypoglycaemia resolved with optimal medical therapy, with a further 25% achieving clinically relevant improvement, however around 30% required transplantation despite access to all therapies. Provision of expertise in hypoglycaemia management is essential to focus limited transplant resources on those who need it most.