Glutamate is an excitatory neurotransmitter in the mammalian central nervous system and a neurotoxin (excitotoxin) that has the potential to destroy neurones by activation of ionotropic receptors. In contrast to the well documented role of glutamate in the pathogenesis of neuronal degeneration resulting from hypoxia/ischaemia, hypoglycaemia, status epilepticus and trauma, it has been difficult to establish a link between the excitotoxicity and neuronal death that occur in chronic neurodegenerative disorders. Impairment of energy metabolism has been shown to increase neuronal vulnerability to glutamate. The cause of this phenomenon lies in the attenuation of the Mg2+ blockade of the N-methyl-D-aspartate receptors that leads to persistent activation of these receptors by physiologic extracellular glutamate concentrations. The concept of increased neuronal vulnerability to excitotoxic injury establishes a link between slow neuronal degeneration and excitotoxicity and suggests that glutamate antagonists may prove beneficial in the treatment of chronic neurodegenerative diseases that have been resistant to therapy.