Adverse drug effects on the gastrointestinal (GI) tract can occur as a predictable result of a drug’s mode of action, by direct injury, through compromising GI defences, or as a consequence of changes in colonic bacterial flora. Non-steroidal anti-inflammatory drugs (NSAIDs) are the commonest cause of gastroduodenal injury, owing to inhibition of prostaglandin synthesis, and increase the risk of serious GI complications between 2.5- and 5-fold. There is considerable variation in risk across the recommended dose ranges for individual NSAIDs. Low doses of aspirin are associated with an increased risk of upper GI haemorrhage. COX-2 inhibitors largely spare the GI mucosa from injury, unless they are co-administered with aspirin when the GI safety benefits are abrogated. As the small intestine becomes more accessible to imaging modalities such as capsule endoscopy, small bowel enteropathy is suggested by hypoalbuminaemia and iron deficiency. Drug-induced colitis is an important problem, with antibiotics the commonest drug cause. Drugs can also exacerbate pre-existing inflammatory bowel disease. Strategies to minimize the adverse GI effects of drugs include giving the lowest dose of NSAID for the shortest time, selective COX-2 inhibitors for high-GI/low-cardiovascular risk patients, and upper GI mucosal protection by co-prescription of NSAIDs with proton pump inhibitors.