In spite of major developments in insulin production, purification, pharmaceutical formulation and methods of delivery, problems remain both in the day to day management of insulin-treated diabetes and with regard to its long-term complications. The risks of hypoglycaemia and weight gain are major concerns particularly for the patient, and the persistence of microvascular and premature macrovascular complications as the main causes of morbidity and mortality in both type 1 and type 2 diabetes is a constant reminder that our therapeutic and management strategies are inadequate. One clear and striking difference between currently available insulin treatments and normal physiology is the relative difference in exposure to insulin of the liver versus peripheral tissues. Hepatoselective insulin analogues have the potential to restore the normal hepatic to peripheral gradient in insulin action. Here, we discuss the possible therapeutic potential that such analogues may have over currently available insulin preparations. These benefits could include a lower risk of hypoglycaemia, less weight gain and a potential reduction in microvascular and macrovascular complications. We explore the evolution of insulin with hepatoselectivity in mind and possible strategies to create hepatoselective insulins.