Adenylyl cyclase activities were measured in mucosal 600 g particulate preparations from the fundic stomach of rats, dogs, rabbits and guinea pigs. In vitro incubation with prostaglandin E1 and NaF activated the enzyme in all species. Pentagastrin and carbachol were ineffective activators in any of the species tested. Histamine activated mucosal adenylyl cyclase activity in the guinea pig but not in any of the other species tested. Histamine antagonists did not conclusively demonstrate the specificity of histamine activated adenylyl cyclase. The universal hypothesis that activation of adenylyl cyclase is the 1st step in the mechanisms of action of gastric acid secretagogues was not supported. Species variability and mucosal tissue heterogeneity appear to constitute difficult problems that must be solved prior to the elucidation of the mechanisms of regulation of acid secretion.