Once the diagnosis of Zollinger-Ellison syndrome has been considered, it is important to ensure the safety of the patient by administering adequate antisecretory medication. There then ceases to be any urgency about the diagnostic work-up. It is essential to establish definitively that the patient has fasting hypergastrinemia and acid hypersecretion to establish the diagnosis of Zollinger-Ellison syndrome. The type of disease (i.e., sporadic or occurring as part of multiple endocrine neoplasia type I) should then be determined by assessment of endocrine function and anatomy because this will influence both the approach to control of acid secretion and the management of the tumor. Assessment of tumor extent and decisions about the management of the tumor can be delayed because these tumors are slow-growing. Because of the rarity of this syndrome, surgical aspects of the management of the disease are best undertaken in centers with particular expertise in this area.