The complex control of food intake and energy metabolism in mammals relies on the ability of the brain to integrate multiple signals indicating the nutritional state and the energy level of the organism and to produce appropriate responses in terms of food intake, energy expenditure, and metabolic activity. Central regulation of feeding is organized as a long-loop mechanism involving humoral signals and afferent neuronal pathways to the brain, processing in hypothalamic neuronal circuits, and descending commands using vagal and spinal neurons. Sensor mechanisms or receptors sensitive to glucose and fatty acid metabolism, neuropeptide and cannabinoid receptors, as well as neurotransmitters and neuromodulators synthesized and secreted within the brain itself are all signals integrated in the hypothalamus, which therefore functions as an integrator of signals from central and peripheral structures. Homeostatic feedback mechanisms involving afferent neuroendocrine inputs from peripheral organs, like adipose tissue, gut, stomach, endocrine pancreas, adrenal, muscle, and liver, to hypothalamic sites thus contribute to the maintenance of normal feeding behavior and energy balance. In addition to transcriptional events, peripheral hormones may also alter firing and/or connection (synaptology) of hypothalamic neuronal networks in order to modulate food intake. Moreover, intracellular energy sensing and subsequent biochemical adaptations, including an increase in AMP-activated protein kinase activity, occur in hypothalamic neurons. Understanding the regulation of appetite is clearly a major research effort but also seems promising for the development of novel therapeutic strategies for obesity.