Despite the introduction of many new antiepileptic drugs during recent years, about one third of the epilepsy population continue to have drug-resistant seizures. We present two hypotheses on mechanisms of drug-resistant epileptic seizures.The article is based on our own clinical experience and literature identified through a PubMed search using the words: refractory, intractable, pharmacoresistant, drug resistant epilepsy/seizures.There is no international consensus on the definition of drug-resistant epilepsy. Some epilepsy types appear to respond to drug treatment, while others are more resistant. Animal models and refractory patients have been studied to find mechanisms that can explain the lack of drug response in some types of epilepsy. Currently, two main hypotheses prevail. The transporter hypothesis implies an over-expression of the proteins (e.g. P-glycoprotein) capable of transporting drugs out of the epileptic focus. The target hypothesis implies changes in receptors or ion channels in the epileptic cellular network, which render this area less susceptible to antiepileptic drugs.Both hypotheses have weaknesses, and alternative theories have been presented. Much remains before the causes of drug-resistant epilepsy are understood. If patients do not achieve seizure control after having tried 2-3 antiepileptic drugs, they should be referred to the national epilepsy centre for a renewed diagnostic evaluation and for consideration of non-pharmacological treatment.