Experiments in acute and chronic animal models of epilepsy provide mechanistic insight into the acute abortive, acute prophylactic, and chronic progressive prophylactic, anti-seizure effects of vagus nerve stimulation (VNS) observed in human epilepsies, and demonstrate antiepileptogenic effects of VNS in the kindling model. Anatomic-physiologic studies, experimental epilepsy studies, and human imaging, EEG, and CSF studies suggest that multiple mechanisms underlie the antiseizure effects of VNS and that alterations of vagal parasympathetic efferent activities do not underlie these antiseizure effects. Putative antiseizure mechanisms are mediated by altered vagal afferent activities, and probably include altered activities in the reticular activating system, the central autonomic network, the limbic system, and the diffuse noradrenergic projection system. Anatomic-physiologic studies fully account for the common and rare adverse effects of VNS. Current understandings of antiepileptic drug (AED) and VNS therapeutic mechanisms strongly support the "common sense" interpretation of the clinical studies: i.e., adjunctive VNS can add antiseizure effect to any AED regimen, with no interactive toxicity and no effect on drug distribution and elimination.