Conscious rats were infused via a jugular vein catheter with 5×10⁻⁶ g/kg/h caerulein for periods up to 24 h. On macroscopic inspection a progressive interstitial oedema is seen to develop in the pancreas, from one hour of infusion on and is most marked at twelve hours. This oedema is largely reabsorbed after 24 h treatment, but the pancreas is considerably indurated by this time. Serum amylase levels increase consistently to reach a tenfold elevation above controls after three, six or twelve hours infusion. Premature fusion of condensing vacuoles and secretory granules leads to formation of large vacuoles in the cytoplasm of exocrine pancreatic cells. These vacuoles fuse with the lateral and basal plasma membrane and realease their content into the extracellular space. Regular discharge of zymogen granules at the cell apex into the duct system does not occur. Vacuole formation is associated with cytoplasmic destruction of the pancreatic cells. The rate of protein synthesis decreases consistently as a result of these structural alterations and this change corresponds largely to a reduction of cellular respiration. Release of amylase from isolated pancreatic lobules of caerulein infused animals shows a progressive increase of unstimulated discharge, while in vitro stimulation with 5×10⁻⁶ M carbamylcholine gives secretion patterns of wash-out kinetics. Stimulated discharge of labeled secretory proteins indicates a progressive reduction in the in vitro sensitivity of the pancreatic cells to secretagogues. After 24 h infusion of 5×10⁻⁶ g/kg/h caerulein the pancreatic lobules are totally insensitive to the in vitro effect of carbamylcholine or caerulein.