AbstractEndoplasmic reticulum (ER) stress is an integral part of life for all professional secretory cells, but it has been studied to greatest depth in the pancreatic β‐cell. This reflects both the crucial role played by ER stress in the pathogenesis of diabetes and also the exquisite vulnerability of these cells to ER dysfunction. The adaptive cellular response to ER stress, the unfolded protein response, comprises mechanisms to both regulate new protein translation and a transcriptional program to allow adaptation to the stress. The core of this response is a triad of stress‐sensing proteins: protein kinase R‐like endoplasmic reticulum kinase (PERK), inositol‐requiring enzyme 1 (IRE1) and activating transcription factor 6. All three regulate portions of the transcriptional unfolded protein response, while PERK also attenuates protein synthesis during ER stress and IRE1 interacts directly with the c‐Jun amino‐terminal kinase stress kinase pathway. In this review we shall discuss these processes in detail, with emphasis given to their impact on diabetes and how recent findings indicate that ER stress may be responsible for the loss of β‐cell mass in the disease. Copyright © 2010 John Wiley & Sons, Ltd.