It is clear that the brain has evolved a mechanism for sensing levels of ambient glucose. Teleologically, this is likely to be a function of its requirement for glucose as a primary metabolic substrate. There is no question that the brain can sense and mount a counterregulatory response to restore very low levels of plasma and brain glucose. But it is less clear that the changes in glucose associated with normal diurnal rhythms and feeding cycles are sufficient to influence either ingestive behavior or the physiologic responses involved in regulating plasma glucose levels. Glucosensing neurons are clearly a distinct class of metabolic sensors with the capacity to respond to a variety of intero- and exteroceptive stimuli. This makes it likely that these glucosensing neurons do participate in physiologically relevant homeostatic mechanisms involving energy balance and the regulation of peripheral glucose levels. It is our challenge to identify the mechanisms by which these neurons sense and respond to these metabolic cues.