The upper gastrointestinal (GI) tract plays a critical role in sensing the arrival of a meal, including its volume as well as nutrient and non-nutrient contents. The presence of the meal in the stomach generates a mechanical distension signal, and, as gastric emptying progresses, nutrients increasingly interact with receptors on enteroendocrine cells, triggering the release of gut hormones, with lipid and protein being particularly potent. Collectively, these signals are transmitted to the brain to regulate appetite and energy intake, or in a feedback loop relayed back to the upper GI tract to further adjust GI functions, including gastric emptying. The research in this area to date has provided important insights into how sensing of intraluminal meal-related stimuli acutely regulates appetite and energy intake in humans. However, disturbances in the detection of these stimuli have been described in a number of eating-related disorders. This paper will review the GI sensing of meal-related stimuli and the relationship with appetite and energy intake, and examine changes in GI responses to luminal stimuli in obesity, functional dyspepsia and anorexia of ageing, as examples of eating-related disorders. A much better understanding of the mechanisms underlying these dysregulations is still required to assist in the development of effective management and treatment strategies in the future.