Hypoglycemia produces complex neural and hormonal responses that restore glucose levels to normal. Glucose, metabolic substrates and their transporters, neuropeptides and neurotransmitters alter the firing rate of glucose-sensing neurons in the ventromedial hypothalamus (VMH); these monitor energy status and regulate the release of neurotransmitters that instigate a suitable counter-regulatory response. Under normal physiological conditions, these mechanisms maintain blood glucose concentrations within narrow margins. However, antecedent hypoglycemia and diabetes can lead to adaptations within the brain that impair counter-regulatory responses. Clearly, the mechanisms employed to detect and regulate the response to hypoglycemia, and the pathophysiology of defective counter-regulation in diabetes, are complex and need to be elucidated to permit the development of therapies that prevent or reduce the risk of hypoglycemia.