The unfolded protein response (UPR) comprises kinase signaling and transcription factor activation cascades delineated over the past 20 years. Most studies conclude that this stress response is adaptive but, nevertheless, includes maladaptive programs involving CHOP expression that drives cell-autonomous apoptosis. Herein, we highlight several studies of UPR diseases involving myelinating glia of the central and peripheral nervous systems that do not support a primary role for CHOP in apoptosis. In oligodendrocytes, CHOP expression apparently protects against death whereas in Schwann cells, CHOP promotes demyelination in the absence of cell death. Together, these studies demonstrate that CHOP should be viewed more broadly as a cell-specific and context-specific mediator of adaptive or maladaptive responses to stress rather than a proapoptotic transcription factor.