The accumulation of misfolded or unfolded proteins in endoplasmic reticulum (ER) lumen results in the activation of an adaptive stress process called the unfolded protein response (UPR). As the most conserved signaling branch of the UPR, Inositol-requiring enzyme 1 (IRE1) possesses both Ser/Thr kinase and RNase activities operating as major stress sensors, mediating both adaptive and pro-apoptotic pathways under ER stress. Over the last three decades, a mounting body of evidence has shown that IRE1 signaling dysfunction is involved in the pathology of various neurological disorders. Targeting this pathway has emerged as a promising therapeutic strategy against these diseases. In this review, we provide a general overview about the expression and physiological function of IRE1 signaling and its pathophysiological roles in the central nervous system diseases.