The Diabetes Control and Complications Trial demonstrated that in patients with type 1 diabetes, tight metabolic control achieved with intensive insulin therapy can reduce the risk of long-term microvascular complications. However, strict glycemic control carries an increased risk of severe hypoglycemia. Recurrent episodes of hypoglycemia, especially at young ages, can lead to hypoglycemia unawareness, exert adverse effects on neurocognitive function, and cause significant emotional morbidity in the child and parents. Although the introduction of the new insulin analogs in diabetes therapy and the use of continuous subcutaneous insulin infusion raised hopes for a solution to this problem, these modalities have not been associated with the expected reduction in hypoglycemic episodes. The findings suggest that the prevention of hypoglycemia in patients with type 1 diabetes lies in biologically controlled insulin secretion, as in islet transplantation, or the development of an autonomous closed-loop system that efficiently mimics the action of the pancreatic beta-cells and maintains blood glucose levels within the desired range.