Resistance to antiepileptic drugs (AEDs) is one of the most serious clinical problems in epilepsy, and along with AED teratogenicity, perhaps the major concern of epilepsy pharmacogenetics. Studying the genetics of drug resistance in epilepsy is important, as it may identify or confirm key mechanisms underlying this phenomenon that have real clinical importance; it might also offer insights into its prediction and management. Drug resistance in epilepsy is likely to be multifactorial: overactivity of multi-drug transporters provides one likely underlying mechanism through lowering of AED concentration in the epileptogenic focus. Genetic association studies may provide a tool to assess this 'transporter' hypothesis by determining whether differences between individuals contribute to resistance phenotypes. Most of these studies have investigated one variant in the ABCB1 gene, and have provided, thus far, inconclusive evidence. This review also considers current knowledge of the role of genetic polymorphisms in multi-drug transporters in pharmacoresistant epilepsy, to highlight possible confounding factors affecting the implementation and interpretation of association studies in this field.