Pharmacoresistant epilepsy poses a therapeutical challenge. There is not an international agreement on how to define pharmacoresistant epilepsy. This makes it difficult to assess why people have pharmacoresistant epilepsy. This article gives an overview on three major hypotheses used to explain the mechanisms of pharmacoresistant epilepsy. The transporter hypothesis proposes that levels of antiepileptic drugs are decreased in the epileptic foci due to an overexpression of drug efflux transporters like P-glycoproteins. It is suggested that P-glycoprotein inhibitors may be used to counteract this effect. The target hypothesis suggests alterations in the antiepileptic drug targets; changes in the GABA-receptors and sodium channels in the epileptogenic brain regions that lead to reduced drug effects are observed. The third hypothesis, the inherent severity model of epilepsy, suggests that there is a continuum of the disease severity, which may lead to pharmacoresistant epilepsy. None of these hypotheses can fully explain pharmacoresistance alone. It is likely that these mechanisms leading to pharmacoresistant epilepsy are interacting. Epilepsy syndromes in children and mesial temporal lobe epilepsy are often associated with pharmacoresistance. Patients who do not experience seizure control should be evaluated at a centre specialized in epilepsy. Treatment alternatives to antiepileptic drug non-responders may be epilepsy surgery or vagus nerve stimulation.