The gastrointestinal tract has a crucial role in the control of energy homeostasis through its role in the digestion, absorption, and assimilation of ingested nutrients. Furthermore, signals from the gastrointestinal tract are important regulators of gut motility and satiety, both of which have implications for the long-term control of body weight. Among the specialized cell types in the gastrointestinal mucosa, enteroendocrine cells have important roles in regulating energy intake and glucose homeostasis through their actions on peripheral target organs, including the endocrine pancreas. This article reviews the biological actions of gut hormones regulating glucose homeostasis, with an emphasis on mechanisms of action and the emerging therapeutic roles of gut hormones for the treatment of type 2 diabetes mellitus.