Ghrelin plays an important role in energy metabolism by regulating food intake, body weight and glucose homeostasis. In this review, we highlight recent developments describing how ghrelin stimulates neuropeptide Y (NPY) neurons, but not pro-opiomelanocortin neurons, to regulate food intake. We describe a novel signaling modality, in which ghrelin activates NPY/agouti-related protein (AgRP) neurons through fatty acid oxidation, reactive oxygen species buffering and mitochondrial function. We hypothesize that this unique system may serve to maintain NPY/AgRP cell function during prolonged negative energy balance. We discuss the idea that the metabolic status plays a key role in ghrelin function. For example, our recent studies illustrate that diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. On the other side of the metabolic coin, ghrelin and GOAT knockout models show that ghrelin is required to maintain blood glucose during severe calorie restriction. We propose the hypothesis that ghrelin primarily functions during negative energy balance to maintain whole-body energy homeostasis.