An important consequence of the many genetic advances that are transforming clinical neurology39 is their ability to suggest new animal models to investigate the underlying disease mechanisms, including compensatory mechanisms that can contribute to a seizure focus.40 Such models are relevant to genetic human epilepsies and serve as an important complement to the acquired models of focal epilepsy (eg, pharmacologically induced seizure models) that have become the mainstay for development of in vivo models of chronic recurring seizures. Animal models of single-gene defects offer an opportunity to evaluate windows for therapeutic intervention in patients who have these specific variants, with the possibility that some therapies will be more broadly applicable to multiple epilepsies. In addition, such models offer a new opportunity to study common mechanisms that underlie maladaptive plasticity and can lead to generation of a seizure focus. Novel gene expression programs may be triggered by genetic deficiencies that engage similar mechanisms, and understanding these might allow better understanding of antiepileptic drug utility.40 In this respect, the intersection of gene expression data sets may inform key pathways that establish seizure foci regardless of the initial genetic defect driving seizures. In addition, genetic animal models can facilitate the evaluation and validation of strategies such as antisense oligonucleotides, gene replacement, and gene augmentation. The success of new genetic treatments of spinal muscular atrophy with intravenously delivered gene replacement via adeno-associated viral vector in very young infants41 has created hope for many patients that these therapies can correct other neurological conditions, stimulating work on this problem in academia and, importantly, in industry. Thus, there are actionable opportunities for genetic therapies for epilepsy on the horizon.