During endoplasmic reticulum (ER) stress conditions, an adaptive signaling network termed the unfolded protein response (UPR) is activated. TheUPR's function is to increaseER protein-folding capacity in order to attenuate ER stress, restore ER homeostasis, and,most importantly, promote cell survival. X-box-binding protein 1 (XBP1) is one component of the UPR and is a proadaptive transcription factor that is subject to transcriptional, post-transcriptional, and post-translational control. In the present study, we identified a post-transcriptional mechanismmediated by miR-34c-5p that governs the expression of both the spliced (active) and unspliced (latent) forms of XBP1mRNAs.Weshowed thatmiR-34c-5p directly attenuates spliced XBP1 (XBP1s)mRNAlevels during ER stress and thus regulates the proadaptive component of the UPR that ismediated by XBP1s without interfering with the induction of apoptotic responses.-Bartoszewska, S., Cabaj, A.,Dabrowski, M.,Collawn, J. F., Bartoszewski, R. miR-34c-5p modulates X-box-binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response. FASEB J. 33, 000-000 (2019). www.fasebj.org.