Tardive dyskinesia (TD) is a serious motor side effect of chronic neuroleptic therapy. TD is a complex hyperkinetic syndrome consisting of choreiform, athetoid or rhythmic abnormal involuntary movements. The face, mouth and tongue are most frequently involved (orofacial type), but a variety of less frequent motor abnormalities of the upper and lower limbs and of the trunk may also occur. TD usually has a delayed onset and the intensity of the syndrome may fluctuate over time. The most serious aspect of TD is that it may persist for months or years after drug withdrawal and in some patients is irreversible. In spite of the prevalence and known etiology that chronic neuroleptic treatment causes TD, relatively little is known about the primary pathological mechanism underlying the condition. Abnormalities in various neurotransmitter systems have been implicated in the pathophysiology of TD, including the dopaminergic, GABAergic, serotonergic and noradrenergic systems. Recently, excitotoxicity of the glutamatergic system and oxidative stress have received much attention. Three general types of animal models have contributed to our knowledge of TD and can be described as homologous, analogous and correlational models. There are no empirically validated guidelines to follow when choosing a suppressive agent. In general, therapeutic trials have attempted to manipulate the dopaminergic, GABAergic, serotonergic and noradrenergic systems, in part due to theories on the pathophysiology of TD. None of these medications has proven successful in the majority of patients. Much more research is needed in order to increase our understanding of TD and to develop better therapeutics for its treatment. (c) 2001 Prous Science. All rights reserved.