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Anti-seizure drugs (ASDs) are the first choice for the treatment of epilepsy, but there is still one-third of patients with epilepsy (PWEs) who are resistant to two or more appropriately chosen ASDs, named drug-resistant epilepsy (DRE). Temporal lobe epilepsy (TLE), a common type of epilepsy usually associated with hippocampal sclerosis (HS), shares the highest proportion of drug resistance (approximately 70%). In view of the key role of the temporal lobe in memory, emotion, and other physiological functions, patients with drug-resistant temporal lobe epilepsy (DR-TLE) are often accompanied by serious complications, and surgical procedures also yield extra considerations. The exact mechanisms for the genesis of DR-TLE remain unillustrated, which makes it hard to manage patients with DR-TLE in clinical practice. Animal models of DR-TLE play an irreplaceable role in both understanding the mechanism and searching for new therapeutic strategies or drugs. In this review article, we systematically summarized different types of current DR-TLE models, and then recent advances in mechanism investigations obtained in these models were presented, especially with the development of advanced experimental techniques and tools. We are deeply encouraged that novel strategies show great therapeutic potential in those DR-TLE models. Based on the big steps reached from the bench, a new light has been shed on the precise management of DR-TLE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)