Several animal models have been developed to investigate the pathobiology of pancreatitis, but few studies have examined the effects that altered pancreatic gene expression have in these models. In this study, the sensitivity to secretagogue-induced pancreatitis was examined in a mouse line that has an altered acinar cell environment due to the targeted deletion of Mist1. Mist1 is an exocrine specific transcription factor important for the complete differentiation and function of pancreatic acinar cells. Mice lacking Mist1 (Mist1^KO) exhibit cellular disorganization and functional defects in the exocrine pancreas but no gross morphological defects. Following the induction of pancreatitis with caerulein, a cholecystokinin analogue, we observed elevated serum amylase levels, necrosis and tissue damage in Mist1^KO mice indicating increased pancreatic damage. There was also a delay in the regeneration of acinar tissue in Mist1^KO animals. Molecular profiling revealed an altered activation of stress response genes in Mist1^KO pancreatic tissue compared to wild type tissue following the induction of pancreatitis. In particular, western blot analysis for ATF3 and phosphorylated eIF2, mediators of ER stress, indicated limited activation of this pathway in Mist1^KO animals compared to wild type controls. Conversely, Mist1^KO pancreatic tissue exhibits increased expression of gadd34 protein, an inhibitor of eIF2 phosphorylation, before and after induction of pancreatitis. These finding suggest that activation of the ER stress pathway is a protective event in the progression of pancreatitis and highlight the Mist1^KO mouse line as an important new model for studying the molecular events that contribute to the sensitivity to pancreatic injury.