Acid secretion (QH+) and oxygen consumption (Qo2) by frog gastric mucosae in vitro were sharply stimulated by lipoate. A rapid decline followed stimulation, subsequently falling below control values. Addition of only glucose or lactate had no effect on Qo2 or QH+. Pyruvate caused slight significant stimulation of Qo2. Any one of these compounds added to lipoate-treated mucosae increased the stimulatory effect of lipoate and markedly slowed the rate of decline subsequent to maximum stimulation. Various fatty acids had a moderate-to-high stimulatory effect on Qo2 and QH+. Lipoate added prior to the addition of fatty acids decreased the stimulatory effect of buryrate (minus 56%), decanoate (minus 87%), and palmitate (minus 60%). Propionate became an inhibitor in the presence of lipoate. Lipoate increased (plus 100%) the amount of glycogen oxidized and decreased (minus 69%) the amount of triglycerides oxidized. Lipoate-treated mucosae did not respond to histamine. Addition of glucose restored responsiveness. The results indicate that beta-oxidation of fatty acids plays a major role in the acid secretory process and is centrally involved in cyclic AMP and histamine stimulation of QH+.