The endoplasmic reticulum (ER) is a key subcellular compartment involved in the folding and maturation of around one‐third of the total proteome. Accumulation of misfolded proteins in the ER lumen engages a signal transduction pathway known as unfolded protein response (UPR) that feedback to recover ER homeostasis or to trigger apoptosis of irreversible damaged cells. The UPR is initiated by three main stress sensors including protein kinase RNA‐like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol‐requiring protein 1α (IRE1α), which reprogram the genome through the control of downstream transcription factors. In this article, the authors have reviewed most relevant studies uncovering the physiological function of the UPR in different organs and tissues based on the phenotypes observed after genetic manipulation of the pathway in vivo. Biomedical applications of targeting the UPR on a disease context are also discussed. © 2013 IUBMB Life, 65(12):962–975, 2013.