Leveraging a gain-of-function mouse model (TRE-XBP1s;Camk2a-tTA [XBP1s-TGNeuron]) and a loss-of-function mouse model (Xbp1fl/fl;Emx1-Cre [Xbp1-cKONeuron]), our group has provided the first evidence that activation of XBP1 signaling in neurons is neuroprotective in both transient and permanent ischemic stroke models, and that activation of the XBP1/HBP/O-GlcNAc axis is a critical mechanism that underpins XBP1-mediated neuroprotection [14,15]. The gene discussed is XBP1; the disease is ischemic stroke.