Abstract: Zollinger‑Ellison syndrome (ZES), a rare endocrine disorder, consists of neuro-endocrine tumors that secrete gastrin, which results in gastric acid hypersecretion and peptic ulcer disease. Since its recognition in 1955 by Dr. Robert Zollinger and Dr. Edwin Ellison as a fulminant peptic ulcer disease in pancreatic tumor patients, its management has evolved significantly over the years. Historically, the only cure for excessive acid secretion was total gastrectomy, despite its high risk of morbidity and mortality. The discovery of histamine‑2 receptor antagonists and proton pump inhibitors transformed the treatment of ZES dramatically by efficiently regulating stomach acid output, thereby improving prognosis and quality of life. While medical treatment stabilized acid production, surgical management has evolved, allowing selective tumor removal guided by advanced localization procedures, including duodenotomy and intraoperative ultrasound. Dr. John W Harmon and his collaborators′ groundbreaking contributions to surgery for ZES have been fundamental in revolutionizing surgical techniques and emphasizing the significance of surgery in maintaining prolonged disease‑free survival. Current management prioritizes personalized treatment, including surgical removal of sporadic gastrinoma, conservative management for multiple endocrine neoplasia type 1‑associated ZES with multiple small lesions, and a multidisciplinary approach for metastatic disease. Recent developments in imaging techniques such as⁶⁸Ga‑DOTA-0-Tyr3-octreotate PET/CT, along with contemporary advancements in treatment with somatostatin analogs, peptide receptor radionuclide therapy, and targeted medications like everolimus and sunitinib, have significantly improved prognosis in advanced cases. The authors provide a thorough analysis of the historical evolution and recent advancements in diagnosing and treating gastrinoma-related ZES, emphasizing the transfor-mation from aggressive surgeries to modern holistic and targeted surgical strategies.