Current perspective on the etiology of common forms of epilepsy reflects clinical and preclinical data that document a complex determinism involving multiple gene variations and environmental influences. This multifactorial architecture precludes effective use of conventional types of genetic analysis and requires application of alternative methods. Presently, such methods are based on candidate gene studies, and it is likely that these approaches will continue to be useful in the near term. Long-range strategies will combine traditional linkage methods with single nucleotide polymorphism gene maps and will seek to collect data on a genomic scale in the search for gene variation that influences both the development of epilepsy and the response to antiepileptic medication. Such studies will require large numbers of patients and controls and also valid, standardized clinical criteria for parsing patients into phenotypic categories. Animal models will continue to provide clues regarding potentially important candidate genes and can also be used in a reverse-translational manner to confirm and study the effects of gene variation that is identified in humans. In the end, genetic research approaches to common forms of human epilepsy will enhance understanding of underlying neurobiological mechanisms, and through this understanding will come new treatment options, new molecular markers to improve current diagnostic criteria, and new genetic tests for predicting drug efficacy in patients with epilepsy.