NMDA receptors (NMDARs) can both protect and kill neurons, depending on their location. Synaptic NMDARs, primarily through nuclear Ca²+ signaling, promote neuroprotection, while extrasynaptic NMDARs promote cell death. These differences arise from distinct genomic programs and opposing signaling pathways. Imbalances between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in conditions like stroke and Huntington's disease. Neuroprotective therapies should enhance synaptic activity and disrupt extrasynaptic death signaling. NMDARs are cation channels gated by glutamate, essential for synaptic plasticity and development. They are found at synaptic, extrasynaptic, and perisynaptic sites. In immature neurons, extrasynaptic NMDARs dominate, but a significant fraction remains extrasynaptic in adults. Extrasynaptic NMDARs are located on dendrites and near glia or axons. Their activation by glutamate spillover may contribute to long-term depression. The 'NMDAR paradox' refers to the dual role of NMDARs in neurotoxicity and survival. Synaptic NMDAR activity promotes neuroprotection through gene expression changes, such as enhancing mitochondrial health and antioxidant defenses. Extrasynaptic NMDARs, however, trigger mitochondrial dysfunction and cell death. Synaptic NMDAR activity activates CREB, a key transcription factor for neuroprotection, while extrasynaptic NMDARs suppress CREB and promote pro-death pathways like Puma and FOXO. Synaptic NMDAR activity also suppresses pro-death transcription factors like Bcl-2 homology domain3 (BH3)-only genes and FOXO, which are involved in apoptosis. It enhances antioxidant defenses by activating the thioredoxin-peroxiredoxin system, which protects against oxidative stress. Extrasynaptic NMDARs, however, activate calpains and STEP cleavage, leading to p38 activation and neuronal death. Extrasynaptic NMDARs can activate pro-death pathways like CREB shut-off, ERK1/2 inactivation, and FOXO activation. These pathways are regulated by the location of NMDARs and the balance between synaptic and extrasynaptic activity. Memantine, an NMDAR antagonist, selectively blocks extrasynaptic NMDAR activity without affecting synaptic signaling, offering a potential therapeutic strategy for neurodegenerative diseases. In Huntington's disease, memantine treatment restored CREB levels and prevented motor deficits in YAC128 mice.NMDA receptors (NMDARs) can both protect and kill neurons, depending on their location. Synaptic NMDARs, primarily through nuclear Ca²+ signaling, promote neuroprotection, while extrasynaptic NMDARs promote cell death. These differences arise from distinct genomic programs and opposing signaling pathways. Imbalances between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in conditions like stroke and Huntington's disease. Neuroprotective therapies should enhance synaptic activity and disrupt extrasynaptic death signaling. NMDARs are cation channels gated by glutamate, essential for synaptic plasticity and development. They are found at synaptic, extrasynaptic, and perisynaptic sites. In immature neurons, extrasynaptic NMDARs dominate, but a significant fraction remains extrasynaptic in adults. Extrasynaptic NMDARs are located on dendrites and near glia or axons. Their activation by glutamate spillover may contribute to long-term depression. The 'NMDAR paradox' refers to the dual role of NMDARs in neurotoxicity and survival. Synaptic NMDAR activity promotes neuroprotection through gene expression changes, such as enhancing mitochondrial health and antioxidant defenses. Extrasynaptic NMDARs, however, trigger mitochondrial dysfunction and cell death. Synaptic NMDAR activity activates CREB, a key transcription factor for neuroprotection, while extrasynaptic NMDARs suppress CREB and promote pro-death pathways like Puma and FOXO. Synaptic NMDAR activity also suppresses pro-death transcription factors like Bcl-2 homology domain3 (BH3)-only genes and FOXO, which are involved in apoptosis. It enhances antioxidant defenses by activating the thioredoxin-peroxiredoxin system, which protects against oxidative stress. Extrasynaptic NMDARs, however, activate calpains and STEP cleavage, leading to p38 activation and neuronal death. Extrasynaptic NMDARs can activate pro-death pathways like CREB shut-off, ERK1/2 inactivation, and FOXO activation. These pathways are regulated by the location of NMDARs and the balance between synaptic and extrasynaptic activity. Memantine, an NMDAR antagonist, selectively blocks extrasynaptic NMDAR activity without affecting synaptic signaling, offering a potential therapeutic strategy for neurodegenerative diseases. In Huntington's disease, memantine treatment restored CREB levels and prevented motor deficits in YAC128 mice.