Approximately one-third of all patients with epilepsy continue to suffer from seizures even after appropriate treatment with antiepileptic drugs. Medically refractory epilepsies are associated with considerable morbidity and mortality, and more efficacious therapies against these disorders are clearly needed. However, the discovery of better therapies has been lagging due to an incomplete understanding of the mechanisms underlying the development of epilepsy (epileptogensis) and seizures (ictogenesis) in humans. An increasing number of studies have suggested that an abnormal amplification of glutamatergic activity--often referred to as the "glutamate hypothesis"--is involved in the pathophysiology of seizures and certain types of medically refractory epilepsies. For example, elevated levels of extracellular glutamate in hyperexcitable areas of the brain, up-regulation of glutamate receptors, and loss of the glutamate-metabolizing enzyme, glutamine synthetase (GS), have all been reported in patients with mesial temporal lobe epilepsy (MTLE). Moreover, it appears that glial cells, particularly the astrocyte, may play a key role in the glutamate overflow in MTLE. Proliferation of astrocytes is a hallmark of the epileptogenic focus in MTLE, and the proliferated cells are characterized by several unique features that are permissive for the excessive accumulation and release of astrocytic glutamate. Here, we assess recent data regarding the glutamate excess in epilepsy, review the role of glutamine synthetase, and discuss the implications of astrocytes in the pathophysiology of MTLE.