Current estimates indicate that up to one-third of all individuals with epilepsy are refractory to antiepileptic drug (AED) therapy. Moreover, most of these people are resistant to multiple drugs with a wide range of mechanistic actions. These observations suggest that the development of multidrug resistance involves nonspecific, global changes in the brain. The multidrug transporter hypothesis of pharmacoresistant epilepsy proposes that regional-specific overexpression of drug efflux transporters in the blood-brain barrier limits the brain penetration of AEDs. Consequently, drug concentrations are too low to induce antiepileptic effects at target brain sites. Cumulative clinical and experimental data support this hypothesis and offer novel therapeutic approaches for the treatment of drug-resistant epilepsy.