Epilepsy afflicts approximately 1% of the population and, although the majority of patients gain effective seizure control through existing medications, a significant number prove refractory to treatment. For intractable focal epilepsies, gene therapy techniques provide a realistic treatment alternative, especially in patients who are considered surgical candidates. Neurotransmitter receptors and ion channels offer attractive gene therapy targets, but the pattern of viral vector transduction and gene expression can dramatically influence the final outcome. Recently, studies have shown that viral vector-mediated transduction and expression of neuroactive peptides, such as galanin and neuropeptide Y, can attenuate seizure sensitivity and prevent seizure-induced cell death in vivo. As future studies define the best means to avoid immunological silencing, as well as establish transduction properties in pathological, epileptic tissue, it should be possible to develop an efficacious gene therapy for intractable focal epilepsy.