Drug resistance is a major clinical problem in epilepsy, affecting one in three patients. It is likely to have a complex multifactorial basis, with environmental and genetic contributions. Knowledge of robust genetic factors underlying drug resistance might both improve prediction and permit the development of novel rational treatments for resistance. A number of genetic association studies have been undertaken examining the effect of a range of candidate genes for resistance. Although some of these candidates have good biologic motivation for mediating resistance, currently there are no common genetic variants proven to generate the common clinical phenomenon of resistance. Much work remains to be done, but the scene is set for exciting developments that will hold therapeutic potential for patients with drug-resistant epilepsy.