Ghrelin regulates hypothalamic circuits to increase food intake by modulating the activity of two neuronal populations in the arcuate nucleus of hypothalamus. Those neurons (NPY/AgRP and POMC) are considered " fi rst-order" sensory neurons in the control of food intake. Ghrelin simultaneously stimulates orexigenic NPY/AgRP neuronal activity and suppresses POMC neuronal activity via inhibitory g -aminobutyric acid (GABA)-eric inputs from active NPY/AgRP neurons. Recent data suggests that metabolic status regulates the function of ghrelin on energy homeostasis and neuronal function and it appears that ghrelin is not able to activate this neuronal circuit in diet-induced obese mice. Contrary to expectations from 10 years ago, ghrelin seems to be more important for the regulation of blood glucose levels during starvation than it is for acute regulation of food intake. This chapter establishes the hypothesis that ghrelin primarily functions during negative energy balance to promote survival. Consistent with this idea, during calorie restriction, ghrelin increases blood glucose and suppresses glucose-stimulated insulin secretion from the pancreas. This important adaptive mechanism prevents insulindriven clearance of glucose from the blood during negative energy balance and thus maintains an immediate energy supply.