Zollinger-Ellison syndrome (ZES) should be suspected if a patient has severe peptic ulceration, ulcers and kidney stones, a family history of ulcers or endocrine diseases, watery diarrhoea or malabsorption with or without ulcers, or if hypergastrinaemia is found. Any patient in whom ZES is suspected, and certainly if diagnosed, should be given large doses of antisecretory medication immediately. This should never be stopped except under controlled conditions or unless acid outputs have been reduced surgically. Patients cannot be managed safely without measuring acid outputs. These should be lowered to < 10 mmol/h, or < 5 mmol/h in patients with a previous gastric resection or severe oesophageal disease. Acid secretion can be controlled acutely in 70% of patients with an infusion of ranitidine 1 mg/kg/h, while 4 mg/kg/h will control acid in all. The initial oral dosage of omeprazole or lansoprazole should be 60 mg/day. Doses should then be adjusted daily on the basis of acid outputs. Proton pump inhibitors in a dosage of 60 mg/day will control acid output in most patients and 60 mg every 12 hours will control acid output in all. Doses can then often be slowly and progressively reduced. A parietal cell vagotomy reduces acid secretion and reduces, but does not abolish, the need for antisecretory medication. In patients with multiple endocrine neoplasia type 1 and hyperparathyroidism, a parathyroidectomy that results in normocalcaemia will reduce acid secretion and drug requirements. A total gastrectomy is rarely if ever needed nowadays. Given the high degree of safety of gastric antisecretory medications versus the risks of acid hypersecretion in patients with ZES, the mistakes in management of acid hypersecretion that must be avoided are those of giving insufficient medication and not measuring acid secretory rates.