Hypoglycemia is a common and serious problem among diabetic patients receiving treatment with insulin or other glucose-lowering drugs. Moderate hypoglycemia impairs neurological function, and severe hypoglycemia leads to death of selectively vulnerable neurons. Recent advances have shed new light on the underlying processes that cause neuronal death in hypoglycemia and the factors that may render specific neuronal populations especially vulnerable to hypoglycemia. In addition to its clinical importance, the pathophysiology of hypoglycemia is an indicator of the unique bioenergetic properties of the central nervous system, in particular the metabolic coupling of neuronal and astrocyte metabolism. This review will focus on relationships between bioenergetics and brain dysfunction in hypoglycemia, the neuronal cell death program triggered by hypoglycemia, and the role of astrocytes in these processes.