Thiamine deficiency is a recognized cause of Wernicke's encephalopathy (WE), a condition in which small necrotic lesions are found in close proximity to the third and fourth ventricles and the Sylvian aqueduct. Although the neuropathology of WE is well-established, the pathogenic mechanisms that determine the formation and distribution of brain lesions identified with this illness are not understood. It is proposed here that glutamate neurotoxicity causes the brain lesions in WE. Glutamic acid decarboxylase (GAD), an enzyme mainly confined to the central nervous system, protects most regions of the brain from glutamate that accumulates when the activity of alpha-ketoglutarate dehydrogenase, a thiamine-dependent enzyme complex, is reduced. During severe thiamine deficiency, glutamate accumulates in GAD-free peripheral tissues and reaches a concentration in blood at which it passes through circumventricular organs into the cerebral ventricles or contiguous brain and finally diffuses into the extracellular space of proximate diencephalic and brain stem tissues. Extracellular glutamate eventually reaches neurotoxic levels in those tissues and causes the characteristic lesions of WE.