This chapter describes a clinical approach of medically refractory epilepsy. Patients with epilepsy whose seizures sometimes not controlled with antiepileptic drug (AED) therapy are number of different terms may be used to describe these includes ‘uncontrolled,’ ‘intractable,’ ‘refractory,’ ‘drug resistant’ or in simple terms drug-resistant epilepsy (DRE). That means seizures continue to occur in spite of treatment with a maximally tolerated dose of a first-line AED as monotherapy or in at least one combination with an adjuvant medication. The terms ‘intractable’ or ‘medically refractory’ are interchangeable. This chapter covers the magnitude of the problem of intractable epilepsy, impact of intractable epilepsy, definition of intractable epilepsy, and causes of refractory epilepsy.