Management of drug resistant epilepsy (DRE) requires a systematic approach consisting of (1) investigation of potential causes of DRE, (2) determination of the degree of DRE on the basis of previous drug therapy, (3) rational pharmacotherapy consisting of both monotherapy and combination therapy, and (4) referral to surgery or other alternative therapy. The scheme of rational pharmacotherapy consists of (1) first drug monotherapy (2) second drug monotherapy, (3) two drug combination therapy, (4) triple drug combination therapy, and (5) addition of second-line drug. With the introduction of many new antiepileptic drugs (AEDs) having different mechanisms of action, the combination therapy has become more effective and safer, which made the use of triple drug combination therapy feasible in practice if it includes at least one new AED. It should be acknowleged that the rational combination therapy may achieve a seizure free outcome in a significant proportion of patients with less severe DRE. For patients with surgically remediable epileptic syndromes, a systematic trial of two to three drugs may suffice an earlier referral to surgery.