Despite the advent of improved insulins, blood glucose monitoring and greater understanding of the pathophysiology, hypoglycaemia continues to be the main factor preventing insulin treated individuals with diabetes from reaching and maintaining glucose targets necessary to prevent long-term complications. The critical dependence of the CNS on a regular supply of glucose means that any significant interruption in glucose delivery can lead to cognitive impairment and coma. Vulnerability to hypoglycaemia is due to acquired defects in the body’s ability to defend itself by releasing glucagon and activating the sympathoadrenal system, critical defences in individuals who cannot regulate insulin secretion. Hypoglycaemia is more frequent and severe among individuals with Type 1 diabetes, but since Type 2 diabetes is more common and because increasing numbers are treated with insulin, hypoglycaemia is a greater clinical problem in this group. As yet, there are no specific therapeutic interventions which can restore impaired counterregulatory protection although strategies which can prevent all episodes of hypoglycaemia may reverse impaired physiological defences, at least in part. Technical advances such as continuous glucose monitoring and closed loop insulin delivery hold promise for the future. However these closed loop devices, islet transplantation or stem cell insulin delivery will not enter the mainstream clinical arena for many years. In the meantime, clinicians (and patients) need to be aware of the limitations of current therapy and do all in their power to minimise the risk of hypoglycaemia.