This review provides an overview of the knowledge on P-glycoprotein (P-gp) and its role as a membrane transporter in drug resistance in epilepsy and drug interactions. Overexpression of P-gp, encoded by the ABCB1 gene, is involved in resistance to antiepileptic drugs (AEDs), limits gastrointestinal absorption and brain access of AEDs. Although several association studies on ABCB1 gene with drug disposition and disease susceptibility are completed to date, the data remain unclear and incongruous. Although the literature describes other multidrug resistance transporters, P-gp is the main extensively studied drug efflux transporter in epilepsy.