Mesial temporal lobe epilepsy (MTLE) is a common neurological disorder characterized by hyperexcitability of limbic structures. Studies in epileptic patients and animal models of MTLE indicate that epileptiform activity arise primarily from limbic areas (e.g. hippocampus) with secondary propagation to cortical areas. A wealth of evidence indicates that epileptiform activity is associated with complex patterns in the expression and function of ion channels, receptors and transporters. Accordingly, several studies portrait MTLE as a post-transcriptional acquired channelopathy. The present review describes the most common features of epileptiform activity emerging from animal models of limbic epileptogenesis and critically discusses the supporting evidence that MTLE is a complex acquired channelopathy.