Cells can respond to perturbations in endoplasmic reticulum (ER) function by activating two distinct signal-transduction pathways: one responds to unfolded proteins, the other to an overload of the organelle with membrane proteins. A third pathway is activated upon sterol depletion of cells and involves the cleavage and subsequent nuclear translocation of an ER membrane-bound transcription factor. Thus, three distinct pathways each activated by a different signal are currently known to project from the ER into the nucleus. This review summarizes the current understanding of these three pathways.