AbstractCellular disturbances that cause accumulation of misfolded proteins in the endoplasmic reticulum (ER) lead to a condition referred to as “ER stress” and trigger the unfolded protein response (UPR), a signaling pathway that attempts to restore ER homeostasis. The complexity of UPR signaling can generate adaptive and apoptotic outputs, depending on the nature and duration of the ER stress. MicroRNAs (miRNAs), small non‐coding RNAs that typically repress gene expression, have recently emerged as key gene regulators of the proadaptive/proapoptotic molecular switch emanating from the ER. Importantly, select miRNAs have been shown to directly regulate key UPR components. © 2013 IUBMB Life, 65(5):373–381, 2013.