NMDA (N-methyl-D-aspartate) receptors are a subtype of ionotropic glutamate receptor with an important role in the physiology and pathophysiology of central neurons. Inappropriate levels of Ca(2+) influx through the NMDA receptor can contribute to neuronal loss in acute trauma such as ischaemia and traumatic brain injury, as well as certain neurodegenerative diseases such as Huntington's disease. However, normal physiological patterns of NMDA receptor activity can promote neuroprotection against both apoptotic and excitotoxic insults. As a result, NMDA receptor blockade can promote neuronal death outright or render neurons vulnerable to secondary trauma. Thus responses to NMDA receptor activity follow a classical hormetic dose-response curve: both too much and too little can be harmful. There is a growing knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of NMDA receptor activity, as well as the factors that determine whether an episode of NMDA receptor activity is harmful or beneficial. It is becoming apparent that oxidative stress plays a role in promoting neuronal death in response to both hyper- and hypo-activity of the NMDA receptor. Increased understanding in this field is leading to the discovery of new therapeutic targets and strategies for excitotoxic disorders, as well as a growing appreciation of the harmful consequences of NMDA receptor blockade.