Traumatic brain injury can produce neurochemical alterations in the brain that are of sufficient magnitude to cause neurological and cognitive deficits. These alterations are associated with a period of excessive neurotransmitter-receptor stimulation involving the N-Methyl-D-aspartate (NMDA) glutamate receptor, as well as other receptors. This abnormal stimulation can produce lasting disruption of neuronal signaling and functional deficits. A number of laboratory studies suggest that NMDA receptor antagonists administered before or soon after traumatic brain injury may provide some protection against pathophysiological effects. The likelihood that functional deficits associated with traumatic brain injury may be at least partly dependent on neurotransmitter-receptor interactions suggests that this component of the injury process may be particularly amenable to pharmacologic treatment. Although a number of highly selective and potent NMDA receptor blockers are available, issues of dosing and toxicity need to be further examined before these agents are considered for human clinical trials.