The gastrointestinal tract, besides digesting and processing nutrients, is now regarded as an endocrine organ able to modulate appetite, satiety, and carbohydrate metabolism. Several enteroendocrine cells produce numerous peptides codifying either orexigenic (ghrelin, orexins) or anorexigenic signals (pancreatic polypeptide, peptide YY, cholecystokinin, amylin, bombesin homologs, apolipoprotein A-IV, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, oxyntomodulin), which interact in a complex network with other peripheral signals of energy balance and with different neuropeptides involved in the central control of appetite and energy homeostasis. The growing knowledge of the actions of these gastrointestinal peptides on appetite regulation and carbohydrate metabolism, and subsequent synthesis of analogs, particularly those derived from amylin and incretins, herald a new era in the therapy of 2 closely related diseases, obesity and type 2 diabetes mellitus.