The N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a Jekyll and Hyde role in the mammalian central nervous system. In pathological scenarios such as ischemia, Ca2+ influx through the NMDA receptor is a key mediator of cell death. However, physiological levels of NMDA-receptor activity can promote neuronal survival and resistance to trauma and play important roles in synaptic plasticity and transmission. This dichotomy may explain the poor tolerance and efficacy of NMDA-receptor antagonists in clinical trials for excitotoxic trauma. There is a growing understanding of the signaling events that mediate the opposing effects of NMDA-receptor activity and the factors that determine whether an episode of NMDA-receptor activity will promote survival or death. This knowledge may lead to therapeutic strategies that enable the selective blockade of prodeath signaling cassettes while sparing physiological signaling to survival and plasticity.