Obesity is an epidemic and medical issue. Investigating the pathways regulating appetite, food intake, and body weight is crucial to find strategies for the prevention and treatment of obesity. In the context of therapeutic strategies, we focus here on the potential of enteroendocrine cells (EECs) and their secreted hormones in the regulation of body weight. We review the role of the enteroendocrine system during weight loss after lifestyle intervention or after bariatric surgery. We discuss the therapeutic potential of EECs and their hormones as targets for new treatment strategies. In fact, targeting nutrient receptors of EECs with a nutritional approach, pharmaceutical agents or prebiotics delivered to the lumen may provide a promising new approach.