It is generally accepted that genetics may be an important factor in explaining the variation between patients' responses to certain drugs. However, identification and confirmation of the responsible genetic variants is proving to be a challenge in many cases. A number of difficulties that may be encountered in pursuit of these variants, such as nonreplication of a true effect, population structure and selection bias, can be mitigated or at least reduced by appropriate statistical methodology. Another major statistical challenge facing pharmacogenetic studies is the detection of possible small polygenic effects using large volumes of genetic data, while controlling the number of false-positive signals. Here, we review statistical design and analysis options available for investigations of genetic resistance to anti-epileptic drugs.