Interactions between secretagogues have been examined by using [¹⁴C]aminopyrine accumulation as an index of the response of isolated canine parietal cells to stimulation. Potentiating interactions were found between histamine and gastrin and histamine and carbachol, but not between carbachol and gastrin. When all three agents were present simultaneously, the response was greater than the sum of the three individual responses and satisfied other criteria for a true three-way potentiation. Against this three-way combination, atropine and cimetidine caused 42 ± 4% and 69 ± 7% inhibition, respectively. When both atropine and cimetidine were added to the three-way combination, the response was inhibited by 84 ± 3%, with the residual response equivalent to that produced by gastrin alone. The phosphodiesterase inhibitor isobutyl methyl xanthine (10 μM) markedly potentiated the actions of histamine. At 10-fold higher concentrations, isobutyl methyl xanthine also potentiated the response to carbachol and gastrin; these effects were inhibited by cimetidine, as had been found previously for. the action of isobutyl methyl xanthine alone. Interference with these potentiating interactions may explain the apparent nonspecificity of atropine and cimetidine in vivo. The striking potency of cimetidine in inhibiting all stimulants of acid secretion in vivo may be explained by the observation that histamine is an essential component of potentiating interactions that determine the parietal cell response to other stimulants.