Five antiepileptic drugs were tested for their ability to block limbic seizures induced by systemic injection of kainic acid and to suppress kainic acid-induced epileptiform discharges in incubated hippocampal slices. Phenytoin, phenobarbital, ethosuximide, and valproic acid inhibited epileptiform discharges in hippocampal slices at concentrations approximating their respective clinically effective anticon-vulsant blood concentration in humans, and diazepam had a similar action at significantly higher concentrations. At these concentrations none of the drugs blocked evoked orthodromic responses of monosynaptic excitatory connections in the hippocampal slices. In contrast, none of the drugs, at therapeutic doses, prevented kainic acid-induced seizure discharges in the hippocampus, in situ. Phenobarbital and diazepam were effective at higher concentrations. These data demonstrate that antiepileptic drugs do not have identical effects on seizure discharges in one type of brain tissue in situ and in vitro even when both are elicited by the same convulsant agent. The results also indicate that limbic seizures induced by kainic acid in vivo, like many cases of complex partial seizures in humans, are highly resistant to conventional anticonvulsant drug therapy.