Why do some patients with epilepsy have good results when they start medication and then lose effectiveness after a period of time? Why do some patients with epilepsy fail to control their seizures even after being treated with several antiepileptic drugs? Although there are many reasons for the poor efficacy of antiepileptic drugs, resistance to antiepileptic drugs is one of the main reasons. The mechanism of antiepileptic drug resistance in refractory epilepsy has been an urgent and difficult problem in the field of epilepsy research. An important clinical feature of patients with refractory epilepsy is resistance to multiple drugs with different mechanisms of action, indicating that the mechanism of antiepileptic drug resistance is a nonspecific mechanism. It has been shown that in addition to cell death and remodeling caused by hippocampal sclerosis and alterations in voltage-gated sodium channels leading to changes in drug target sensitivity contribute to the development of drug resistance in epilepsy, there is also an overexpression of drug transporters in the lesioned tissue. Drug transporters are proteins that can transport a variety of drugs and are mainly found at sites with secretory and barrier functions, such as the blood-brain barrier and the blood-cerebrospinal fluid barrier, and the common transporters are: 1. receptor-mediated transporters; 2. carrier-mediated transporters including P-gp (P-glycoprotein), MRPs (multidrug resistance-associated proteins), nucleoside transporters, organic anion transporters, and large amino acid transporters, the latter three of which have transport substrates mainly related to the synthesis of substances in the brain. Since drugs for CNS diseases must cross the blood-brain barrier to reach their targets, the blood-brain barrier transporters may play an important role in the development of CNS drug resistance. Under physiological conditions, it exerts its detoxification and maintains the stability of the intracerebral environment through the blood-brain barrier, which is a kind of self-defense and protection of the organism. However, under pathological conditions, its expression is increased in diseased tissues and is non-selective for the transport of certain substances. Currently, overexpression of drug transporters has been found to be enhanced in refractory epileptic brain tissues, and it has been found that epileptic tissues may differ from other tissues in that they allow upregulation of drug transporter expression such as P-gp, and the upregulation results in a decrease in extracellular antiepileptic drug concentrations in the focal area, and phenytoin sodium, carbamazepine, lamotrigine, phenobarbital, and felbamate have been found to be P-gd, MRP1, and MRP2 transport substrates. In addition, the high expression of multidrug resistance gene protein (MDR1) in brain tissue is one of the factors most closely associated with drug resistance formation. MDR1 is an ATP energy-dependent membrane pump that pumps most drugs, including antiepileptic drugs, and even some toxicants out of the cell to form drug resistance. It has been shown that the common pathological features of refractory epilepsy are degenerative neuronal damage and reactive astrocyte proliferation, but this pathological change is seen in a range of cerebral hypoxic-ischemic diseases, so it can be speculated that the frequent seizure process in refractory epilepsy may be a factor that can lead to cerebral ischemia and hypoxia. It has been found that there is high expression of MDR1 in reactive astrocytes in refractory epilepsy, and this high expression leads to reduced intracellular concentrations of antiepileptic drugs. Nanotechnology is the science and technology of individual molecules or atoms to make novel structures or miniature devices. Novel drug delivery modalities can improve the efficacy and safety of antiepileptic drugs, commonly drug delivery nanosystems, precursor drugs, and inhibition of multidrug resistance proteins that allow antiepileptic drugs to efficiently aggregate at the lesion and maintain therapeutic concentrations. Liposomes, nanotechnology or multimers can be used as carriers. And multimeric nanoparticles ensure the stability and safety of biodegradation and achieve controlled release of their contents. Nanotechnology offers promising prospects for the treatment of epilepsy, but the technology also has safety issues, such as the possibility of some nanoparticles generating free radicals that are destructive to cells. In conclusion, the mechanism of antiepileptic drug resistance is more complex and many questions remain unsolved, so there is still a long way to go to move from experimental research to clinical practice.