Gastric acid has been thought to be an important cause of disease and complaints for many hundred years. Combined with the relatively easy access to gastric juice, it is not surprising that physiology in many ways was started in the stomach. Beaumont studied the regulation of gastric acid secretion in one patient with gastric fistula, Pavlov did the first studies on living animals in his fistula dogs and gastrin was the second hormone to be postulated, the second to be purified and sequenced, and the second to be determined by radioimmunoassay. Since 1920 we have known of the three principal gastric secretatgogues; acetylcholine, gastrin and histamine. However their interaction was disputed until the end of the last century .After Gregory and Tracy purified gastrin it was shown to stimulate acid secretion and to be released by meal. The physiological role of histamine was doubted until Black described the histamine-2 receptor and Håkansson described the ECL cell as the cell producing the histamine that participates in the regulation of gastric acid secretion. Berglund and Öbrink developed isolated oxyntic glands and isolated parietal cell preparations and assessed acid secretion by the accumulation of aminopyrine. They found that histamine and cholinergic drugs, but not gastrin stimulated acid secretion. American authors continued to produce indications for a direct effect of gastrin on the ECL cell. We developed the totally isolated vasucularly perfused (with erythrocytes) rat stomach into production of acid and could show that maximal histamine stimulated acid secretion exceeded maximal gastrin stimulated secretion, and that a cholinergic drug in contrast to gastrin, further augmented acid secretion. With the help of a sensitive histamine radioimmunoassay we could show that gastrin induced an immediate release of histamine of a magnitude sufficient to explain the acid stimulation. From a functional point of view it was therefore no need for a gastrin receptor on the parietal cell. When using a fluorescein labeled gastrin analogue in the isolated stomach we thereafter could show that gastrin did bind only to the ECL cell and not the parietal cell and even not to the stem cell. Gastrin has since the fifties been known to have a trophic effect on the oxyntic mucosa. However, hypergastrinemia was subsequently shown to specifically affect the growth of the ECL cell as demonstrated by ECL cell carcinoids in patients with hypergastrinemia. In rats we could show that the trophic effect of gastrin on the ECL cell showed the same concentration dependence as the functional effect, and in long-term studies where we did differential counting of the cell types in the oxyntic mucosa, we noticed a marked increase in ECL cell and a moderate and similar effect on the other cell types, again a strong argument for no gastrin receptor on the parietal cell. Long-term hypergastrinemia induces ECL cell hyperplasia resulting in an increase in gastrin-stimulated histamine release .Since gastrin-stimulated histamine release is the restrictive factor for gastrin (meal) stimulated acid secretion, it would be expected that a period with hypergastrinemia in patients with normal oxyntic mucosa will result in increased acid secretion. In 1996 we described how a 3-months period with proton pump inhibitor (PPI) resulted in rebound acid hypersecretion which we claimed to be the cause of the problems in stopping PPI therapy. A few years ago Reimers and co-workers in Denmark described that PPI dosing of healthy young persons induced dyspepsia. It has for long been known that patients with pernicious anemia are prone to develop gastric carcinoids and even gastric adenocarcinomas. ECL cell carcinoids also develop in patients with gastrinoma having hypergastrinemia without hypoacidity, and it is well known that long-term hypergastrinemia in rodents predisposes to gastric neoplasia. We have recently shown that ECL cell carcinoids secondary to atrophic gastritis regress during treatment with the gastrin antagonist netazepide. The role of the ECL cell in human gastric carcinogenesis is probably much greater than previously thought. Thus, the re classification from gastric adenocarcinomas to neuroendocrine (and in the stomach it is mainly ECL cell origin) carcinomas has been done in rodents (Mastomys, rats, cotton rats) for many years. By using immunohistochemistry with increased sensitivity (tyramide signal amplification) and in situ hybridization (RNAScope) we have been able to show that a substantial part of gastric carcinomas of diffuse type according to Lauréen is of ECL cell origin and that virtually all gastric carcinomas in patients with pernicious anemia are ECL cell derived. Together with these new gains in gastric physiological knowledge, the identification of Helicobacter pylori (HP) as a central pathogen for the upper gastrointestinal tract has increased our understanding of these diseases. Thus, HP infecting the antral mucosa causes duodenal ulcer by an inappropriate stimulation of gastrin release, resulting in a slight but sufficient hypergastrinemia to induce elevated gastric acid secretion. These patients never develop marked hypergastrinemia and are protected from gastric cancer. When affecting the oxyntic mucosa, HP infection causes atrophy of the glands giving hypoacidity and thus a marked hypergastrinemia which predisposes to ECL cell neoplasia.