Hypoglycemia is a life-threatening side effect of intensive insulin therapy in Type 1 diabetic patients. The ability to detect hypoglycemia and restore blood glucose levels to normal is of critical concern to the brain since glucose is its preferred fuel. When plasma glucose levels fall, powerful hormonal and sympathoadrenal mechanisms respond to restore blood glucose levels to normal. These mechanisms are believed to be initiated by diverse populations of glucose sensors, which are located centrally as well as peripherally. The exact contribution of each of these individual glucose sensors to the regulation of glucose homeostasis is not known at this time. This review focuses on the diversity of central and peripheral glucose sensors and the mechanisms by which they sense glucose.