The human brain generally uses glucose as its principal metabolic fuel but cerebral metabolism and function during hypoglycaemia can be supported by a variety of substrates. Different brain regions may vary in this. The brain's ability to sense a falling blood glucose concentration and initiate a protective response varies according to prior glycaemic experience. The brain's ability to use non-glucose fuels may ultimately be of therapeutic use. Meanwhile, avoidance of even moderate hypoglycaemia during normal clinical treatment of diabetes mellitus leads to restoration of protective symptomatic responses to early hypoglycaemia, without necessarily causing a deterioration in overall glycaemic control.