1. Caerulein produced a striking increase in the rate of secretion of the guinea-pig pancreas. When tested in vivo with pancreatic slices its optimal concentration was found to be 2.5 ng/ml. In vivo the intravenous injection of 400 ng/kg and the subcutaneous injection of 4 mug/kg of the drug produced marked secretory responses.2. Neither incubation of pancreatic slices in vitro for various lengths of time in the presence of caerulein nor the intravenous injection of the drug brought about any detectable changes in the rate of (14)C-L-leucine incorporation into protein of pancreatic slices incubated in vitro. By contrast, a two-fold increase in the incorporation of leucine was found in fasting animals injected subcutaneously with caerulein twice a day for 4 days. The same treatment in fed animals, or one single dose of caerulein injected subcutaneously 4 h before killing in guinea-pigs starved for 4 days did not affect the rate of incorporation. Moreover the long term treatment with the cholinergic segretagogue bethanechol in fasted guinea-pigs was also ineffective.3. It is concluded (a) that in the guinea-pig pancreas, stimulation of enzyme secretion does not affect per se the rate of synthesis of digestive enzymes; and (b) that the increase of protein synthesis elicited by caerulein is critically dependent both on the nature of the segretagogue (that is, it is elicited by the polypeptide but not by a cholinergic drug) and on the experimental conditions (it is evident only in fasted animals after prolonged treatment).