Advances in the understanding of mechanisms underlying the pathophysiology of epilepsy have led to the identification of sodium hydrogen exchanger (NHE) as one of the possible targets for future antiepileptic drugs (AEDs). There are indicators from several experimental studies that NHE inhibitors could be of significant value as potential anticonvulsants. Various in-vitro reports (brain slices) have suggested anticonvulsant potential of these agents. Recently we provided the in-vivo data on anticonvulsant efficacy of amiloride (an NHE inhibitor) in different animal models of seizure and epilepsy. In addition to blocking NHE, these agents are known to affect other traditional targets like voltage-gated Na+ channels, Ca2+ channels, glutamate concentration, etc. Thus NHE inhibitors may represent a novel class of AEDs and surely deserve more scientific attention. In this review, we focus on the role of NHE in epilepsy and provide the experimental evidence available so far on the effect of NHE inhibitors in various animal models.