Significance The endoplasmic reticulum (ER) is the site for folding and maturation of secreted and membrane proteins. When the ER protein-folding machinery is overwhelmed, misfolded proteins trigger ER stress, which is frequently linked to human diseases, including cancer and neurodegeneration. Inositol-requiring enzyme 1 (IRE1) is an ER membrane-resident sensor that assembles into large clusters of previously unknown organization upon its activation by unfolded peptides. We demonstrate that IRE1 clusters are topologically complex dynamic structures that remain contiguous with the ER membrane throughout their lifetime. The majority of clustered IRE1 molecules are diffusionally trapped inside the clusters until IRE1 signaling attenuates, at which point they are released back into the ER through a pathway that is functionally distinct from cluster assembly.