The capacity to fold proteins properly is fundamental for cell survival. Secreted and transmembrane proteins are synthesized in the endoplasmic reticulum (ER), an organelle that has the ability to discriminate between native and nonnative proteins, in a process called protein quality control. When folding is not properly achieved, misfolded proteins can accumulate. The terminally misfolded proteins are typically retrotranslocated into the cytoplasm for degradation by the proteasome, in a process known as endoplasmic reticulum-associated degradation. However, if the degradation is insufficient, accumulation of abnormal proteins in the ER activates the unfolded protein response (UPR), a complex set of new signals aimed to reduce further the load of abnormal protein in the ER. Massive synthesis of myelin lipids and proteins is necessary to support myelinogenesis. Not surprisingly, therefore, ER stress (including the UPR), the proteasome, and autophagy (lysosomes) have been implicated in myelin disorders, such as Pelizaeus-Merzbacher disease and vanishing white matter disease in the central nervous system and Charcot-Marie-Tooth neuropathies in the peripheral nervous system. Here we discuss recent evidence supporting an important role for ER stress in myelin disorders.