Although there are numerous definitions of drug resistance in epilepsy it is generally accepted that drug resistance occurs when seizures persist in the presence of an optimal antiepileptic treatment. In spite of many newer antiepileptic drugs introduced into treatment, the relative number of drug-resistant patients remains approximately the same and reaches 30%. Consequently, there are a great deal of experimental and clinical studies aimed at finding mechanisms responsible for this phenomenon. Characterization of these mechanisms could result in new, more efficient treatment strategies.To review experimental and clinical data on possible mechanisms of drug resistance in epilepsy.An increased expression of protein drug transporters (for example, P-gp or MRP) within the blood-brain barrier or in the epileptic focus itself seems an important mechanism of drug resistance. This leads to the enhanced removal of antiepileptic drugs from the brain and subsequently, their reduced concentrations in the target tissue. Also, mutations of genes encoding GABAA receptors or ion channels may be reasons for the diminished protection of antiepileptic drugs. Some role may be ascribed to the genetic polymorphism of liver microsomal enzymes. Last but not least, use of other drugs unrelated to epilepsy (i.e. theophylline) or ingestion of stimulatory substances (f.e. caffeine) are likely to reduce the protective potential of antiepileptic drugs.In animal models of epilepsy, inhibitors of drug transporters (verapamil, probenecid) efficiently inhibit drug resistance--may be, this potential method of treatment will be positively verified in clinical trials. Initial clinical data on this issue are encouraging. Probably, the drug resistance due to methylxanthines could be stopped quite easy by replacement of this drug group with other drugs sharing other mechanisms of action and exerting similar clinical effects. The most challenging for an efficient treatment seems drug resistance due to genetic reasons.