The effect of systemic and intracerebral injections of kainic acid, a potent neuroexcitatory and neurotoxic analogue of glutamate, has been studied in the rat using a variety of light- and electron-microscopic techniques. Systemic injections of 12 mg/kg produce a high incidence of 'wet dog shakes' and convulsions; seizure activity is consistently associated with neuronal damage. The initial neuropathological reactions include dendritic and glial dilations in discrete areas of the neuropil; at this time and subsequently, affected neuronal somata either appear swollen and pale, or are shrunken with dark cytoplasm. In the most severely affected areas, the lesion progresses to severe disruption of the neuropil. A vvidespread pattern of damage is seen throughout the forebrain, which is relatively consistent from brain to brain and is characterized by the parallel degeneration of pairs or groups of structures with extensive axonal interconnections. The commonly affected areas include the olfactory cortex, amygdaloid complex, hippocampus, and related parts of the thalamus and neocortex. Intracerebral injections of 2-6 nmol produce extensive neuronal damage in distant structures, as well as at the injection site. The pattern of distant damage varies with the site of the injection and appears to reflect axonal connections between the affected areas near the injection and the distant areas of damage. For example, injections into the olfactory cortex tend to produce damage in the amygdala, the mediodorsal thalamic nucleus, and related areas of the frontal cortex, as well as in the olfactory cortex itself. Injections into the posterior part of the olfactory cortex which involve the entorhinal cortex tend to produce severe degeneration in field CA1 of the hippocampus, although field CA3 is more severely damaged following intraventricular, intrahippocampal or intrastriatal injections. These observations suggest that kainic acid may exert at least part of its toxic effects via axonal connections. Furthermore, the widespread damage induced by intracerebral injections indicates that caution must be exercised in the use of kainic acid to produce circumscribed lesions, and that careful histological evaluation of such lesions is required.