Glucose homeostasis is of paramount concern to the brain since glucose is its primary fuel. Thus, the brain has evolved mechanisms to sense and respond to changes in glucose levels. The efferent aspects of the central nervous system response to hypoglycemia are relatively well understood. In addition, it is accepted that the brain regulates food intake and energy balance. Obesity and diabetes both result from and cause alterations in the central nervous system function. Thus, it is reasonable to hypothesize that the brain also regulates daily glucose homeostasis and energy balance. However, little is known about how the brain actually senses and responds to changes in extracellular glucose. While there are neurons in the brain that change their action potential frequency in response to changes in extracellular glucose, most studies of these neurons have been performed using glucose levels that are outside the physiologic range of extracellular brain glucose. Thus, the physiologic relevance of these glucose-sensing neurons is uncertain. However, recent studies show that glucose-sensing neurons do respond to physiologic changes in extracellular glucose. This review will first investigate the data regarding physiologic glucose levels in the brain. The various subtypes of physiologically relevant glucose-sensing neurons will then be discussed. Based on the relative glucose sensitivity of these subtypes of glucose-sensing neurons, possible roles in the regulation of glucose homeostasis are hypothesized. Finally, the question of whether these neurons are only glucose sensors or whether they play a more integrated role in the regulation of energy balance will be considered.