Epilepsy is a recurrent, often progressive neurological disorder with a chronic evolution, affecting 1 to 2 % of the world population. Research with experimental models and imaging analysis of diseased patients have been used to show that recurrent episodes produce oxidative stress, most of which is related to neuronal excitability phenomena. It is known that the excessive stimulation of glutamate receptors results in neurotoxicity; a process that, under the denomination of excitotoxicity, is thought to constitute the principal cellular death mechanism behind different disorders of the central nervous system, including epilepsy. Paradoxically, although the signaling pathways, molecular mechanisms and sites of action of excitotoxicity have received considerable attention since the 1970s, little is known about their relevance to CNS disorders. Further detail is necessary about the fundamental role of neuronal death and the mechanisms, particularly those relevant to neurological pathogenesis, that are engaged whenever glutamate receptors are excessively stimulated, as the results would aid considerably the development of timely clinical interventions delaying the evolution of these disorders. We review clinical and experimental data on the relevant alterations of the glutamatergic system, cell death pathways, and the activation of caspases and members of the Bcl-2 gene family involved in the process as modulators of cell death during epilepsy. The findings support the hypothesis that excitotoxic processes as well as both apoptotic and necrotic neuronal cell death phenomena converge in drug-resistant epilepsy.