An adequate supply of nutrients is obligatory for life. Glucose is one of the main circulating substrates fuelling the mammalian body, particularly brain, and is normally maintained within a narrow range to ensure health. Given the challenge of maintaining glucose homeostasis, mammals have evolved specialized sensors for monitoring changes in glucose availability. Glucose sensors are distributed centrally and peripherally. Hypothalamic glucose sensors are arousing burgeoning research interest particularly as a result of increasing evidence that the hypothalamus plays an important role in the control of glucose homeostasis. During the last decade, knowledge of hypothalamic glucose sensors has greatly improved, especially as a result of transgenic mice technology and other advances in molecular genetic approaches. This review provides a broad overview of the relevance of hypothalamic glucose sensors in the physiological regulation of glucose homeostasis and putative pathophysiologic relevance to glycaemic diseases. The primary focus of this report has been to discuss recent data suggesting novel roles for hypothalamic glucose sensors in the control of hepatic glucose production, insulin secretion and hypoglycemia counterregulation. Finally, an improved understanding of hypothalamic glucose sensing pathways may be pertinent for an integral comprehension of the regulation of glucose homeostasis and associated disorders.