The management of seizures in the patient with epilepsy relies heavily on antiepileptic drug (AED) therapy. Fortunately, for a large percentage of patients, AEDs provide excellent seizure control at doses that do not adversely affect normal function. At the molecular level, the majority of AEDs are thought to modify excitatory and inhibitory neurotransmission through effects on voltage-gated ion channels (e.g., sodium and calcium) and gamma-aminobutyric acid (GABA)(A) receptors, respectively. In addition to these effects, two of the "second-generation" AEDs have been found to limit glutamate-mediated excitatory neurotransmission (i.e., felbamate and topiramate). Not surprisingly, those AEDs with broad spectrum clinical activity are often found to exert an action at more than one molecular target. Emerging evidence suggests that receptor and voltage-gated subunits are modified by chronic seizures. Thus, attempts to understand the relationship between target and effect continue to provide important information about the neuropathology of the epileptic network and to facilitate the development of novel therapies for the treatment of refractory epilepsy.