Publisher Summary Glutamate plays a key role in the initiation and spread of seizure activity. Focal administration of glutamate into different brain structures, and focal or systemic administration of more potent glutamatergic agonists, such as N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or kainic acid, cause convulsions in experimental animals in vivo and epileptiform activity in in vitro cell- and slice-preparations. Glutamate also acts on neuronal and glial metabotropic receptors. Metabotropic receptors can be categorized into three classes of receptors depending on pharmacological diversity and coupling to second messenger systems. Activation of different classes of metabotropic receptors can result in both convulsant and anticonvulsant action. Glutamatergic synapses play a critical role in all epileptic phenomena. Broadly enhanced activation of post-synaptic glutamate receptors (ionotropic and metabotropic) is proconvulsant. Antagonists of NMDA receptors and AMPA receptors are powerful anticonvulsants in many animal models of epilepsy. Many different alterations in glutamate receptors or transporters can potentially contribute to epileptogenesis.