Epilepsy imposes a significant clinical, epidemiologic and economic burden on societies throughout the world. Despite the development of more than ten new antiepileptic drugs over the past 15 years, approximately a third of patients with epilepsy remain resistant to pharmacotherapy. Individuals who fail to respond, or respond only partially, continue to have incapacitating seizures. Managing patients with medically refractory epilepsy is challenging and requires a structured multidisciplinary approach in specialized clinics. If the problems related to drug resistance could be resolved, even in part, by improving the pharmacokinetic profile of existing drugs, the economic savings would be remarkable and the time required to design drugs that achieve seizure control would be shorter than the discovery of new targets and molecules was required. A promising approach is the use of corticosteroids that may have a dual beneficial effect. Resective brain surgery remains the ultimate and highly successful approach to multiple drug resistance in epileptic patients.