It is long-established that high levels of NMDA receptor activity kill neurons. Acute excitotoxic events such ischemia, mechanical trauma or epileptic seizure can also lead to excessive extracellular glutamate accumulation and cell death. Even chronic neurodegenerative diseases have been associated with toxic levels of NMDA receptor activity. The potentially destructive effects of excessive NMDA receptor activity are in marked contrast to the more recent findings that synaptic NMDA receptor activity can promote neuronal survival and resistance to trauma (Hardingham, 2006). Thus, neuronal responses to glutamate or NMDA follow a bell-shaped curve: both too much and too little NMDA receptor activity is potentially harmful (Hardingham and Bading, 2003). In treating neurological or neurodegenerative disorders associated with pro-death NMDA receptor signalling, it would be desirable to be able to interfere with pro-death signalling from the NMDA receptor, while not affecting pro-survival signalling, or signalling to synaptic plasticity. While death and survival signaling pathways are both activated by calcium influx, a greater knowledge as to the spatial calcium requirements to activate these pathways may aid in their selective inhibition, and enhance our understanding of the dichotomous nature of NMDA receptor signalling. If calcium effectors of survival and death were located in different parts of the cell, potentially requiring different protein-protein interactions, this may point to more specific ways of selectively targetting pro-death events. Analysis of NMDA receptor-dependent activation of the pro-death stress-activated kinases (JNK and p38) revealed that they require spatially distinct subcellular pools of calcium from those required to activate survival signalling to CREB and Akt. Moreover, neuroprotective disruption of p38 signalling could be achieved by uncoupling the NR2B PDZ ligand from downstream proteins by using intracellular peptides mimicking the NR2B PDZ ligand. The effectiveness of this peptide in reducing NMDA receptor dependent excitotoxicity in vitro can be achieved without inhibiting NMDA receptor dependent neuroprotection or synaptic plasticity. The in vivo effectiveness of this peptide compared to other therapeutic anti-stroke strategies will also be discussed. In conclusion, the dichotomous death/survival signals that emanate from the NMDA receptor have spatially distinct calcium requirements and are amenable to selective inhibition.