Disturbance of endoplasmic reticulum (ER) proteostasis causes cellular dysfunction. ER stress activates unfolded protein response (UPR), a set of signal transduction pathways, which restore protein homeostasis through the regulation of protein synthesis, quality control, and degradation. The UPR is implicated in many central nervous system (CNS) diseases such as neurodegenerative diseases and brain insults. While much research has focused on neurons, the spatiotemporal changes in the UPR in pathogenesis and the importance of the UPR in other cells are still poorly understood. We recently found a unique feature of UPR induction after brain injury using ER stress-activated indicator (ERAI) mice, which can monitor the UPR by detecting the activity of an ER stress transducer with green fluorescence. The reporter signals were observed in damaged neurons in the early phase after brain injury. However, the majority of the cells positive for the ERAI signals were non-neuronal cells such as vascular endothelial cells and astrocytes throughout the period analyzed after injury. Another approach to elucidating the significance of the UPR showed that conditional deletion of the UPR sensor/transducer in glia exacerbated neurodegeneration after CNS injury. These findings shed light on the importance of the UPR in the non-neuronal cells. In this talk, I will present recent findings and discuss the potential of the UPR as a therapeutic target to control CNS pathologies.