The past decades have brought several advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs (AEDs), more than one-third of patients are resistant to pharmacological treatment. Furthermore, current AEDs do not prevent the development and progression of epilepsy. Thus, there is an urgent need to develop new therapies for AED-resistant patients, for prevention of epilepsy in patients at risk and for disease modification. Cell replacement and gene therapies have been proposed to offer potential approaches for improvements in therapy, but are such approaches really more promising than new pharmacological strategies? Here we critically review and discuss data from epilepsy models and human tissue studies indicating that cell and gene therapies might provide alternative therapeutic approaches for AED-resistant focal epilepsies and might have antiepileptogenic or disease-modifying potential. However, several crucial issues remain to be resolved to develop cell and gene therapies into effective and safe therapies.