The odyssey of Zollinger-Ellison Syndrome is one of the most interesting in surgery. From the initial recognition of two patients with severe peptic ulcer disease in 1955 sprung an international dialogue on this unique disease culminating in discovery that gastrin was the hormone secreted by these pancreatic and duodenal tumors. The impact was the birth of a new area of science, “gastrointestinal endocrinology.” Initially, surgeons were challenged by the complexity of the patients and the need to perform total gastrectomy to prevent death from complications of the severe ulcer disease. Later, after the discovery of proton pump inhibitors, total gastrectomy was no longer needed and the surgeon could focus treatment on tumor removal added by radioimmunoassay for gastrin and new imaging modalities. Today, we recognize that all gastrinomas have malignant potential; early surgical removal can reduce the incidence of metastases and improve survival, independent of biochemical cure, in both sporadic and familial forms of the disease.