In 1984, Reg protein was shown to be stimulated during the regeneration of pancreatic islets. Since then, many Reg-related proteins have been identified in humans and other animals. These Reg-related proteins are classified into four subfamilies according to their amino-acid sequences, but they share a similar structure and physiological function. The role of Reg in gastric tissue was investigated, and Reg I was found to be expressed mainly in gastric fundic enterochromaffin-like (ECL) cells. Reg I production in ECL cells is stimulated by gastrin, as well as by the proinflammatory cytokine, cytokine-induced neutrophil chemoattractant (CINC)-2Beta. In patients with chronic hypergastrinemia, Reg production is stimulated, with the increased proliferation of gastric mucosal cells. Patients with Helicobacter pylori infection also showed increased Reg production in the gastric mucosa, partly via increased plasma gastrin concentration and partly via increased proinflammatory cytokine production. Thus, Reg protein induced by H. pylori infection may be partly responsible for the increased proliferation of gastric epithelial cells in H. pylori-infected patients. Reg protein is also produced in many gastric cancer cells, especially in poorly differentiated and advanced cancers. Reg protein stimulates the proliferation of several gastric cancer cell types, and gastric cancers with Reg protein expression tend to show a poorer clinical outcome. In summary, Reg protein may be a growth factor that regulates the proliferation and differentiation of normal and neoplastic gastric epithelial cells.