Food intake and energy expenditure are tightly regulated by the brain, in a homeostatic process that integrates diverse hormonal, neuronal and metabolic signals. The gastrointestinal tract is an important source of such signals, which include several hormones released by specialized enteroendocrine cells. These hormones exert powerful effects on appetite and energy expenditure. This Review addresses the physiological roles of peptide YY, pancreatic polypeptide, islet amyloid polypeptide, glucagon-like peptide 1, glucagon, oxyntomodulin, cholecystokinin and ghrelin and discusses their potential as targets for the development of novel treatments for obesity.