Drug-resistant epilepsy remains a challenge in the therapeutic management of patients with epilepsy. Identification of factors contributing to drug resistance might render a basis for the development of novel therapeutic approaches, for the reorganization of screening programs in drug development, and for the design of personalized treatment concepts. Therefore, experimental and clinical studies need to link efforts and collaborate in order to elucidate drug-resistance mechanisms, to define the relative clinical relevance of selected mechanisms, and to develop and validate novel therapeutic concepts in overcoming resistance.