The gastrointestinal (GI) tract, the key interface between ingested nutrients and the body, plays a critical role in regulating energy homeostasis. Gut-derived signals convey information regarding incoming nutrients to the brain, initiating changes in eating behavior and energy expenditure, to maintain energy balance. Here we review hormonal, neural and nutrient signals emanating from the GI tract and evidence for their role in controlling feeding behavior. Mechanistic studies that have utilized pharmacological and/or transgenic approaches targeting an individual hormone/mediator have yielded somewhat disappointing bodyweight changes, often leading to the hormone/mediator in question being dismissed as a potential obesity therapy.