A critical role for the gut in energy homeostasis has emerged. Gut hormones not only have a role in digestion but several of them have been found to modulate appetite in animals and humans. Current nonendocrine drugs for obesity are limited by their modest efficacies, and bariatric surgery is confined to use in severe cases. The discovery of important appetite-signaling pathways from the gut to the brain has led to the emergence of several gut hormone-derived drugs that are being investigated for clinical use. This article summarizes the physiology of the major gut hormones implicated in appetite regulation, and reviews clinical evidence that gives us insight into their potential as clinical treatments for obesity.