Epilepsy affects approximately 3% of the population. Majority of epileptic patients may control their crisis with anticonvulsant drugs, however, 30%-40% became refractory to pharmacological therapies and could require surgical treatment. The causes of pharmacological refractoriness are poorly understood. Multidrug-resistance (MDR) mechanisms observed in cancer, could be also present in Refractory Epilepsy (RE). The ATP-binding-cassette (ABC) transporters may develop MDR phenotype preventing anti-epileptic drugs (AEDs) to reach their parenchyma brain targets. MDR-1 gene encoded P-glycoprotein (P-gp), is constitutively expressed in excretory tissues, including vascular endothelial cells (VEC) of the blood-brain-barrier. Here, we describe several MDR proteins over-expressed in VEC, astrocytes and neurons from adults and pediatric RE patients. Surgically treated cases showed brain P-gp over-expression with persistent plasmatic low levels of AEDs, and/or accelerated 99mTc-MIBI hepatic-clearance. Experimentally, we observed that a sequential and progressive seizures-induced P-gp over-expression from VEC → astrocytes → neurons correlated with increasing refractoriness to phenytoin treatment. Clinically and experimentally, we observed that nimodipine reverts RE phenotype. Because P-gp depolarizes potential membrane of P-gp-expressing tumor-cells, we hypothesized that weaker glutamic stimulation may totally depolarizes to P-gp-expressing neurons, inducing persistent low convulsive-threshold and playing a role in epileptogenesis mechanisms Pharmacological control of ABC-transporters could avoid the current invasive surgical treatments for Refractory Epilepsy.