The role of central and peripheral histamine H-3 receptors in the regulation of gastric acid secretion and gastric mucosal integrity is reviewed. The activation of H3 receptors by peripheral administration of the selective agonist (R)alpha -methylhistamine reduced acid secretion in cats, dogs, rats and rabbits, while increasing it in mice. The antisecretory effects were observed against indirect stimuli that act on vagal pathways or on enterochromaffin-like (ECL) cells, such as 2-deoxy-D-glucose, food or pentagastrin, but not against histamine or dimaprit. Inhibitory effects on acid production were observed in rats after central administration of histamine or of H-3 receptor agonists. In the conscious rat intragastric administration of (R)alpha -methylhistamine caused gastroprotective effects against the damage induced by absolute ethanol, HCl, aspirin and stress. The mechanism involved seems to be related to the increased mucus production, via nitric oxide-independent mechanisms. Gastroprotective effects against ethanol were also observed after central administration of histamine or its metabolite N-alpha-methylhistamine, suggesting that brain H-3 receptors participate in the histamine-mediated effects on gastric functions.