Epilepsy is a common chronic neurological disease. The International League Against Epilepsy (ILAE) defines seizures as: the transient occurrence of signs or symptoms due to abnormally excessive or synchronous neuronal activity in the brain. About 70% of patients achieve seizure-free with appropriate medical treatment, but nearly one-third of patients still do not respond to current antiepileptic drugs (AEDs). The alpha subunits of voltage-gated sodium channels (VGSCs) are encoded by a highly conserved gene family, of which mutations in SCN1A, SCN2A, and SCN8A genes are important causes of central nervous system diseases. Previous studies have shown that voltage-gated sodium channels play an important role in the pathological process of treatment-resistant epilepsy (TRE). In this paper, the concept, pathogenesis and drug resistance mechanism of treatment-resistant epilepsy were introduced in detail, meanwhile the role and mechanisms of voltage-gated sodium channels in treatment-resistant epilepsy were reviewed.