Accumulation of misfolded protein in the endoplasmic reticulum (ER) triggers an adaptive stress response-termed the unfolded protein response (UPR)-mediated by the ER transmembrane protein kinase and endoribonuclease inositol-requiring enzyme-1α (IRE1α). We investigated UPR signaling events in mice in the absence of the proapoptotic BCL-2 family members BAX and BAK [double knockout (DKO)]. DKO mice responded abnormally to tunicamycin-induced ER stress in the liver, with extensive tissue damage and decreased expression of the IRE1 substrate X-box-binding protein 1 and its target genes. ER-stressed DKO cells showed deficient IRE1α signaling. BAX and BAK formed a protein complex with the cytosolic domain of IRE1α that was essential for IRE1α activation. Thus, BAX and BAK function at the ER membrane to activate IRE1α signaling and to provide a physical link between members of the core apoptotic pathway and the UPR.