Control of eating in mammals is part of the homeostatic regulation of energy stores, metabolites and essential nutrients. Meal initiation and termination result from peripheral signals that originate in the oral cavity (orosensory stimuli), in the gastrointestinal (GI) tract (stomach distension, nutrients, osmolality), and from the metabolization of absorbed nutrients. The central nervous system integration of the corresponding neural (afferent nerve activity) and humoral (e.g. GI peptides) signals shapes the behavioral (eating) and autonomic (metabolism) output. Several GI peptides influence eating mainly by acting in a paracrine fashion on afferent nerves in the wall of the GI tract, but some may also modulate eating through an endocrine effect. Hepatic portal glucose sensors affect eating, insulin release and, hence, metabolism. Hepatic fatty acid oxidation (FAO) also has been proposed to influence eating. Recent data, however, suggest a role of small intestinal enterocytes rather than hepatocytes as FAO sensors in the control of eating; further studies are necessary to identify the underlying mechanism and to examine its specificity and potential physiological relevance. In addition to these meal-related control mechanisms, endocrine adiposity signals, presumed to reflect the body's energy stores (e.g. leptin, insulin), affect eating and metabolism by acting directly in the brain. The central nervous system integration of all these peripheral signals occurs in a complex neuronal network with nodes in the brainstem (in particular in the nucleus tractus solitarii = NTS, where many meal-related signals enter the brain), the midbrain (in particular in the hypothalamus, where adiposity signals are registered), and in the forebrain (where several areas are involved in food-related learning and reward processes). Adiposity signals modulate the meal-related signals in part through descending projections from the hypothalamus to the NTS. Together, these regulatory mechanisms maintain energy homeostasis, i.e., long-term stability of body weight within an individual range.