1. The role of extracellular HCO3- and H+ in the formation of primary saliva and its subsequent modification by the glandular ducts has been investigated in the isolated perfused mandibular salivary gland of the rabbit. 2. Variation of extracellular HCO3- concentration between 12.5 and 50.0 mmol/l was without effect on salivary flow rate or on Na+ and K+ excretion, even though salivary HCO3- (and Cl-) content altered with changes in the extracellular concentration of the two anions. 3. Complete replacement of perfusate HCO3- by Cl- reduced fluid secretion by 34% and almost abolished ductal Na+ absorption. However, when extracellular pH was controlled by replacing HCO3- with the hydrophilic HEPES buffer, fluid secretion but not ductal Na+ absorption was restored to normal. 4. Complete replacement of exogenous HCO3- with acetate increased fluid secretion by 110% and also stimulated ductal Na+ absorption. This effect did not appear to be related to changes in cell pH and remains unexplained. Acetate entered the saliva in concentrations comparable to those seen for HCO3- in control experiments. 5. Salivary secretion showed an almost linear dependence on extracellular pH, rising from 14% of control (pH 7.4) levels at pH 6.2 to 130% at pH 7.8. Ductal Na+ absorption showed similar pH dependence. 6. Carbonic anhydrase inhibitors did not affect fluid secretion rates (except when supramaximal doses of ACh were used to evoke secretion) but they did cause a large reduction in salivary HCO3- output. In glands perfused with acetate rather than HCO3-, carbonic anhydrase inhibitors had no effect on excretion of fluid, acetate or metabolically derived HCO3-. Duct perfusion studies suggested that the effect of the inhibitors on HCO3- output was at the site of primary secretion rather than at the ductal site of HCO3- transport.