The aim of epilepsy treatment is to achieve complete seizure freedom. Nonetheless, numerous side effects and seizure resistance to antiepileptic drugs (AEDs) affecting about 30–40% of all patients are main unmet needs in today’s epileptology. For this reason, novel approaches to treat epilepsy are highly needed. Herein, we highlight recent progress in stem-cell–based and gene transfer–based therapies in epilepsy according to findings in animal models and address their potential clinical application. Multiple therapeutic targets are described, including neuropeptides, neurotrophic factors, and inhibitory neurotransmitters. We also address new molecular-genetic approaches utilizing optogenetic technology. The therapeutic strategies presented herein are predominately aimed toward treatment of partial/focal epilepsies, but could also be envisaged for targeting key seizure propagation areas in the brain. These novel strategies provide proof-of-principle for developing effective treatments for refractory epilepsy in the foreseeable future.