Epilepsy characterized by recurrent behavioral seizures, affects approximately 1% of the population worldwide. More than one-third of epilepsy patients are estimated to have pharmacoresistant epilepsy. One-half of patients with refractory epilepsy are characterized as having mesial TLE with foci in the amygdaloid complex, hippocampus, and surrounding cortex. In 50-70% of such cases, surgical removal of the temporal lobes can successfully treat the disease, however, it is not always applicable because of the presence of secondary foci and localization of primary foci in the deep brain. A recent therapeutic approach focuses on the delivery of botulinum neurotoxins directly into the seizure focus in the brain and this approach is currently being investigated using animal models. Several reports have demonstrated that botulinum neurotoxin E injected into the hippocampus of rat with KA-induced epileptic rats prevents neuronal loss in the CA1-subfield of the hippocampus and the dentate granule cell dispersions, and glutamate release from the hippocampal synaptosomes. Furthermore, injection following the acquirement of KA-induced spontaneous recurrent seizures reduces chronic seizures. We provide a plausible mechanism of action of botulinum neurotoxin action in the CNS and discuss the possibility of its therapeutic application to human epilepsy.