The protein kinase PERK couples protein folding in the endoplasmic reticulum (ER) to polypeptide biosynthesis by phosphorylating the α subunit of eukaryotic translation initiation factor 2 (eIF2α), attenuating translation initiation in response to ER stress. PERK is highly expressed in mouse pancreas, an organ active in protein secretion. Under physiological conditions, PERK was partially activated, accounting for much of the phosphorylated eIF2α in the pancreas. The exocrine and endocrine pancreas developed normally in Perk−/− mice. Postnatally, ER distention and activation of the ER stress transducer IRE1α accompanied increased cell death and led to progressive diabetes mellitus and exocrine pancreatic insufficiency. These findings suggest a special role for translational control in protecting secretory cells from ER stress.