Epilepsy represents a major burden to society, not least because approximately 25% of patients do not respond satisfactorily to antiepileptic medication, and only a minority with pharmacoresistant epilepsy are eligible for potentially curative surgery. Several studies have explored gene therapy as a treatment strategy. The translation of scientific breakthroughs into the clinic faces several challenges, including the validation of experimental models of human pharmacoresistant epilepsy, establishment of sensitive and specific measures of therapeutic efficacy, and evaluation of the long-term safety of gene therapy. On the basis of successful reports of gene therapy in experimental models of epilepsy, a roadmap toward clinical trials is proposed.