Gastrin is the most important peptide in the regulation of gastric acid secretion. This communication reviews important new developments in our knowledge of its synthesis, action, and pathophysiology. The gene for human gastrin has been isolated, and it encodes a pre-pro-gastrin which is a 101-aminoacid peptide containing within it the structure of big gastrin (G34) with a C-terminal glycine extension. Post-translational processing by alpha-amidation of the glycine-extended progastrin results in generation of the active forms of the peptide (G34, G17). When gastrin binds to its receptor on the parietal cell, phosphatidylinositol biphosphate (IP2) in the plasma membrane is converted to inositol 1,4,5-triphosphate (IP3), which acts as the secondary intracellular messenger to increase intracellular calcium and initiate the process that eventually leads to acid secretion. Although an abnormality in gastrin release or action is not thought to be crucially important in the genesis of duodenal ulcer, these patients nevertheless demonstrate increased postprandial gastrin release, and a greater sensitivity of their parietal cells to gastrin. Hypergastrinemia is the cause of peptic ulceration in the Zollinger-Ellison syndrome, in primary gastrin cell hyperplasia or hyperfunction, and in the retained antrum syndrome. Ulcerogenic hypergastrinemia must be distinguished from hypergastrinemia that is secondary to hypoacidity or anacidity, as is seen in atrophic gastritis or postvagotomy.