Data in support of the role of histamine and cAMP as mediators of acetylcholine-induced acid secretion in frog gastric mucosa are presented. The notion that acetylcholine-induced alkaline secretion is mediated by cGMP is supported. Tissue cAMP and cGMP and rates of acid secretion and histamine release were measured in in vitro preparations of frog gastric mucosa that were stimulated by acetylcholine. A transient increase in each variable was observed, the sequence of transient maxima being histamine release, cGMP, cAMP and acid secretion. Atropine, an anticholinergic agent, eliminated all 4 transient increases, the variables remaining at resting levels. Metiamide, a H2-antagonist, modified the changes observed after acetylcholine stimulation. The acid secretion transience was abolished and the transient increase in tissue cAMP was greatly diminished, but the tissue of cGMP transience and histamine release transience were unchanged. A model is proposed in which acetylcholine initiates 2 different processes, acid and alkaline secretions.