Mesial Temporal Lobe Epilepsy is a severe form of epilepsy in adults that often cannot be controlled with antiepileptic drugs. Considering the fact that epilepsy is one of the most common neurological disorders, pharmacoresistance is a major health issue. Insights into the mechanisms that are involved in pharmacoresistance may ultimately lead to a therapy for pharmacoresistant epilepsy patients. The aim of the research described in my thesis is to investigate the role of the blood-brain barrier and multidrug transporters in pharmacoresistant epilepsy, using a rat model for temporal lobe epilepsy. My thesis provides evidence that multidrug transporters play an important role in pharmacoresistance by reducing antiepileptic drug levels in specific brain regions and shows that seizures can be controlled by pharmacological inhibition of multidrug transporters. Alternatively, an anti-epileptic drug that is not transported by multidrug transporters (levetiracetam) also initially controlled seizures. However, the effects of both these therapeutic approaches were transient. The development of tolerance indicates that, in addition to overexpression of multidrug transporters, other mechanisms of pharmacoresistance are relevant. Future research should therefore not be limited to multidrug transporters but should also include anti-epileptic drug properties and their targets.