Mutations in ion channels can cause rare monogenetic epilepsies. While most cases of epilepsy are likely polygenic in inheritance, investigations of how disease causing mutations in channels change neuronal activity have provided a trove of new insights into the mechanisms of epilepsy. These insights are increasingly making it feasible to develop mechanistically-based gene therapy order to stop seizures even in patients who do not have mutations in ion channels. The approach used in our group emerged from work with collaborators studying mutations in KCNA1, which encodes Kv1.1 channels. Mutations in KCNA1 are extremely rare, and are more typically associated with episodic ataxia type 1 (EA1) than with epilepsy (1,2). Control data used to determine the functional consequences of mutant Kv1.1 subunits expressed in cultured neurons, revealed that over expression of non-mutant Kv1.1 channels reduced both neuronal excitability and transmitter release(3). Importantly, over-expression of Kv1.1 in these cultures did not appear to trigger homeostatic changes to counteract the reduction of activity caused by Kv1.1. These findings suggested that over-expression of Kv1.1 may be capable of reversing some of the increased excitability that is observed in neurons in epileptic foci. In vivo, lentiviral expression of Kv1.1 reduced the excitability of Layer V neurons in the motor cortex, with more current required to reach threshold, and a significant decrease in number of action potentials fired over a range of current injections compared to non-transduced neurons. Neurons over-expressing Kv1.1 did not have hyperpolarised resting potentials, and the shape of individual action potentials was largely unaffected(4). Lentiviral treatment affected a relatively small number of neurons in a constrained space (<1 mm3), as is expected from the relatively large size of the lentiviral particles. However, EEG recordings indicated that in spite of the small area of expression, lentiviral delivery of Kv1.1 was sufficient to reduce high frequency epileptiform activity in the tetanus toxin model of focal neocortical epilepsy. Kv1.1 gene therapy treatment reduced the signatures of epilepsy in the EEGs of treated animals, even when administered after seizures were established. Overexpression of Kv1.1 effectively cured epilepsy in these animals. Kv1.1 emerged as a candidate treatment from studies a rare but genetically tractable disease. In some ways this channel is also theoretically a predictable choice for reversing the excess excitability seen in neurons in epileptic tissue (5). However, other Kv channels may be more obvious choices based on pure biophysics. Many more channels, including endogenous, exogenous and synthetic channels also represent candidates for developing mechanistically-based gene therapies(6,7). Gene therapy treatments informed by studies of monogenetic channelopathies may be effective even in patients with epilepsy who have no known disease causing mutations.