Neurons expressing agouti-related protein (AgRP), the so-called hunger neurons, protect mammals from starvation by promoting food-seeking behaviors (Trends Neurosci 36:504-512, 2013). Now an increasing amount of evidence show that these hunger-sensing neurons not only motivate animals to forage and ingest food but also help conserve energy by inhibiting innate processes that demand large amounts of energy such as growth, reproduction, and stress response. It has further been perceived that AgRP neurons transmit signals with negative valence to reward and cognitive centers so as to engage the motivational behavior toward seeking and obtaining foods (Physiol Behav 190:34-42, 2017). Recent advancement in genome editing and neurotechniques unleashed an escalated research of uniquely defined neuronal populations and neural circuits underlying the behavioral regulation of body weight and food responses (Nat Biotechnol 32:347-355, 2014; Proc Natl Acad Sci 113, 2016). In this chapter we will review literatures describing the functional organization of the AgRP circuit and its correlative signaling components that influence ingestive, foraging, motivational, and cognitive responses, a framework that reshaped our thinking toward the new hope and challenges in treatment of obesity and eating disorders.