Ca2+ influx through the NMDA (N-methyl-D-aspartate) subtype of ionotropic glutamate receptors plays a Jekyll and Hyde role in the mammalian central nervous system. While it mediates excitotoxic death triggered by stroke and other acute trauma, there is growing evidence that physiological levels of NMDA receptor activity promote survival. Understanding the mechanisms that underlie these opposing effects may lead to strategies to selectively block pro-death signalling, which could have considerable clinical benefits.