Gene therapy may constitute a promising alternative to conventional pharmacological tools and surgeries for epilepsy. For primary epilepsy, a single variant leading to a significant effect is relatively rare, while other forms are considered complex in inheritances with multiple susceptible mutations and impacts from the environment. Gene therapy in preclinical models of epilepsy has attempted to perform antiepileptogenic, anticonvulsant, or disease-modifying effects during epileptogenesis or after establishing the disease. Creating gene vectors tailored for different situations is the key to expanding gene therapy, and choosing the appropriate therapeutic target remains another fundamental problem. A variety of treatment strategies, from overexpressing inhibitory neuropeptides to modulating the expression of neurotransmitters or ion channels, have been tested in animal models. Additionally, emerging new approaches of optogenetics and chemogenetics, as well as genome-editing tools will further boost the prosperity of gene therapy. This review summarizes the experience obtained to date and discusses the challenges and opportunities in clinical translations.