Secretory and transmembrane proteins are correctly folded or processed in the endoplasmic reticulum (ER). Various stresses disturb ER function and provoke the accumulation of unfolded proteins in the ER lumen. This condition is termed ER stress. Recently, ER stress has been linked to neuronal death in various neurodegenerative diseases. Among the cell populations in the nervous system, which comprises heterogeneous cell types including neuronal and glial cells, astrocytes have the unique ability of being able to tolerate and even proliferate under ischemic and hypoxic conditions that lead to ER stress. This review introduces a novel ER stress transducer, old astrocyte specifically induced substance (OASIS), that regulates the signaling of the un-folded protein response specifically in astrocytes and contributes to resistance to ER stress. In addition, current information is summarized regarding new types of ER stress transducers homologous to OASIS that are involved in cell type-specific ER stress responses.