Epilepsy is a commonly encountered disorder among neurological disorders in our country and in the world. Almost 30% of seizures persist in spite of medical treatment. Resistance to medical treatment is important with regard to cognitive and psychosocial problems, and increased risk in mortality and morbidity. It may emerge due to the type of epilepsy, underlying epileptogenic process, and individual differences. Immunological, genetic and plasticity-related mechanisms are most relevant. The literature related to this subject is growing constantly, and increased understanding of the underlying mechanisms of drug resistance will play an important role in the development of more efficient treatment strategies. Contributing to this body of work, this article discusses drug resistance in epilepsy, its underlying mechanisms and accompanying clinical issues.