The unfolded protein response (UPR) is a cell-signaling system that detects the accumulation of unfolded protein within the endoplasmic reticulum (ER) and initiates a number of cellular responses to restore ER homeostasis. The presence of unfolded protein is detected by the ER-luminal sensor domains of the three UPR-transducer proteins IRE1, PERK, and ATF6, which then propagate the signal to the cytosol. In this review, we discuss the various mechanisms of action that have been proposed on how the sensor domains detect the presence of unfolded protein to activate downstream UPR signaling.