Obesity is a global health concern yet licensed non-surgical therapies are of limited efficacy and alternatives are needed. Harnessing the body’s own appetite-regulating signals is a desirable pharmacological strategy. The gastrointestinal tract is the largest endocrine organ in the body producing hormones that have important sensing and signalling roles in regulating body weight and energy expenditure. Indeed, the last decade has witnessed a marked increase in our understanding of the role of gut hormones in energy homeostasis. Dietary modifications, such as altering macronutrient composition and/or restricting caloric intake, are the first-line obesity treatments. However, dieting results in only moderate weight-loss and maintenance of weight-loss is poor. Compensatory gut hormone changes induced by dieting may contribute to the failure of weight-loss through dietary means. In contrast, bariatric surgery is an efficacious treatment modality for obesity, resulting in durable weight loss and amelioration of obesity-associated co-morbidities, particularly type 2 diabetes mellitus. Moreover, the metabolic benefits of bariatric surgery occur independently of weight loss. There is increasing evidence that surgically induced alterations in circulating gut hormones mediate the weight-loss and metabolic beneficial effects of bariatric surgery. Consequently, strategies aimed at modulating circulating gut hormone concentrations or targeting their receptors are being developed as potential pharmacotherapies for obesity.