Conditions that compromise protein folding in the endoplasmic reticulum trigger the unfolded protein response (UPR), which either restores proper protein folding or results in cellular demise through apoptosis. In this study, we found that, in response to ER stress in vivo and in vitro, PKCδ translocates to the ER where it binds to the tyrosine kinase Abl. Tyrosine phosphorylation and kinase activity of PKCδ are required for PKCδ binding to Abl in the ER. Moreover, we found that inhibition of PKCδ by the PKCδ-specific peptide inhibitor δV1-1 or by silencing of PKCδ reduces ER-stress-induced JNK activation and inhibits ER-stress-mediated apoptosis. Furthermore, the inhibitor of PKCδ kinase activity rottlerin blocks the translocation of the PKCδ-Abl complex from the ER to the mitochondria and confers protection against apoptosis. Thus, PKCδ communicates ER stress to the mitochondria by binding to ER-localized Abl. The PKCδ-Abl complex then translocates to the mitochondria, communicating ER stress to this organelle, thereby, triggering apoptosis.