The transmucosal potential difference (PD), the rate of H+ secretion and the net flux of potassium from nutrient to secretory phases (JnsK) of the frog gastric mucosa were studied in vitro by the chamber method. Histamine produced a fall in PD, a sustained increase in H+ production and an equivocal rise in JnsK. Increasing the nutrient potassium concentration (Kn) to 8.5 mEq/l. in the presence of histamine induced a depression in PD, although the rate of acid secretion was unchanged. Hydrogen ion secretion decreased when the nutrient potassium concentration was decreased to 1 mEq/l. despite the continued presence of histamine. The response of JnsK to alterations in nutrient potassium concentration was unaffected by the presence of either histamine or thiocyanate. Thiocyanate produced almost complete inhibition of H+ secretion and a rise in PD. Raising the nutrient potassium concentration in the presence of thiocyanate produced a prompt and sustained fall in PD, followed by a transient rise when Kn was lowered. Alterations of the nutrient potassium concentration in the presence of thiocyanate had no effect on the rate of acidification. The data indicate that under certain circumstances PD and H+ secretion can be uncoupled and that the inverse relationship between Kn and PD is substantially independent of the rate of H+ secretion.