Epilepsy is the most common chronic neurological disease, affecting approximately 65 million people worldwide, with mesial temporal lobe epilepsy (mTLE) being the most common type, characterized by the presence of focal seizures that begin in the hippocampus and subsequently generalize to structures such as the cerebral cortex. It is estimated that approximately 40% of patients with mTLE develop drug resistance (DR), whose pathophysiological mechanisms remain unclear. The neuronal network hypothesis is one attempt to understand the mechanisms underlying resistance to antiepileptic drugs (AEDs), since recurrent seizure activity generates excitotoxic damage and activation of neuronal death and survival pathways that in turn promote the formation of aberrant neuronal networks. This review addresses the mechanisms that are activated, perhaps as compensatory mechanisms in response to the neurological damage caused by epileptic seizures but that affect the formation of aberrant connections that allow the establishment of inappropriate circuits. On the other hand, glia seem to have a relevant role in postseizure plasticity, thus supporting the hypothesis of the neuronal network in drug-resistant epilepsy, which has been proposed for ELT.