A third of patients continue to have seizures using existing antiepileptic drugs, demonstrating the need for novel therapeutic approaches. Although the use of gene therapy to decrease neuronal excitability has shown promise in preclinical models, it is irreversible and may interfere with normal brain function. Now, Lieb et al. describe an autoregulatory antiepileptic lentiviral-based gene therapy which inhibits neurons in response to pathological accumulation of extracellular glutamate. In a rat model of focal epilepsy, the therapy decreased seizures without adverse effects.