Generalized seizures are commonly thought to involve the entire brain homogeneously. However, recent evidence suggests that selective cortical-subcortical networks may be crucial for the initiation, propagation, and behavioral manifestations of generalized seizures, while other brain regions are relatively spared. Here we review previous studies, and describe a new human model system for the investigation of generalized seizures: single-photon emission computed tomography, ictal-interictal difference imaging of generalized tonic-clonic seizures induced by electroconvulsive therapy (ECT). Bitemporal ECT activates focal bilateral frontotemporal and parietal association cortex, sparing other regions; bifrontal ECT activates mainly prefrontal cortex; while in right unilateral ECT the left frontotemporal region is relatively spared. Associated midline subcortical networks are also involved. Focal verbal memory deficits parallel the focal regions involved in these neuroimaging studies. Further studies of this kind may elucidate specific networks in generalized tonic-clonic seizures, providing targets for new therapeutic interventions in epilepsy.