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1. NaCl in the bathing medium of the isolated rabbit pancreas has been gradually replaced by isotonic amounts of either sucrose, choline chloride or KCl. 2. The replacement of NaCl always leads to a reduction in pancreatic flow. This reduction is largest with sucrose as replacing agent and smallest with KCl. 3. The Na+ concentration in the secreted fluid decreases only slightly when NaCl is replaced by sucrose. In the experiments with choline chloride, the Na+ concentration in the secreted fluid decreases slightly when less than 60 mM-NaCl has been replaced, but decreases markedly after more extensive NaCl replacement. Upon replacement of NaCl by KCl, the Na+ concentration in the secreted fluid is always equal to that in the bathing medium. 4. The K+ concentration in the secreted fluid increases by 8 mM upon replacing NaCl by either sucrose or choline chloride. Upon replacement by KCl the K+ concentration in the secreted fluid is always approximately equal to that in the bathing medium. 5. There is a linear relationship between the ratio of the K+ concentrations in the secreted fluid and the bathing medium and the ratio of the Na+ concentrations in these fluids. 6. Replacement of NaCl in the bathing medium does not lead to a change in the transepithelial potential. 7. The secreted fluid is always isotonic with that of the bathing medium; in the case of an extensive replacement of NaCl by either sucrose or choline chloride isotonicity is maintained by a higher cation concentration and an increased appearance of the replacing agents in the secreted fluid. 8. These studies confirm previous findings that extracellular Na+ is essential for pancreatic fluid secretion. 9. They also indicate that the monovalent cations reach the secreted fluid through a paracellular pathway. 10. These findings are incorporated in a model for the electrolyte movements involved in the pancreatic fluid secretion by ductular as well as by acinar cells.