The concept of the gut forming the centre of an integrated gut–brain–energy axis — modulating appetite, metabolism and digestion — opens up new paradigms for drugs that can tackle multiple symptoms in complex upper gastrointestinal disorders. These include eating disorders, nausea and vomiting, gastroesophageal reflux disease, gastroparesis, dyspepsia and irritable bowel syndrome. The hormones that modulate gastric motility represent targets for gastric prokinetic drugs, and peptides that modify eating behaviours may be targeted to develop drugs that reduce nausea, a currently poorly treated condition. The gut–brain axis may therefore provide a range of therapeutic opportunities that deliver a more holistic treatment of upper gastrointestinal disorders.