Abstract.Histamine 0–1 µM‐0.1 mM increased adenylate cyclase activity five‐ to ten‐fold in human fundic membranes, with a potency Ka = 3 µM. The histamine dose‐response curve was mimicked by the H3receptor agonist (R) α‐MeHA, but at 100 times lower potency, Ka = 0.3 mM. Histamine‐induced adenylate cyclase activation was abolished by H2, H1and H3receptor antagonists, according to the following order of potency IC50:famotidine (0.3 µM)>triprolidine (0.1 mM) thioperamide (2 mM), respectively. Famotidine has no action on membrane components activating the adenylate cyclase system, including the Gs subunit of the enzyme stimulated by forskolin and cell surface receptors sensitive to isoproterenol (β2‐type), PGE2and VIP. The Schild plot was linear for famotidine (P<0.01), with a regression coefficientr= 0.678. The slope of the regression line was 0.64 and differs from unity. Accordingly, famotidine showed a slow onset of inhibition and dissociation from the H2receptor in human cancerous HGT‐1 cells. The results demonstrate that famotidine is a potent and selective H2receptor antagonist with uncompetitive actions in human gastric mucosa. Consequently, famotidine might be a suitable drug with long‐lasting actions in the treatment of Zollinger‐Ellison syndrome. The results also confirm and extend the previous observations that (R) α‐MeHA and thioperamide are two selective ligands at histamine H3receptor sites. In the human gastric mucosa, these drugs are respectively 330 and 6700 times less potent than histamine and famotidine on the adenylate cyclase system. The possible involvement of histamine H3receptors in the regulation of