Many patients with epilepsy can be successfully treated with a single antiepileptic drug (monotherapy). However, in a substantial number of patients, monotherapy does not provide satisfactory seizure control, and the use of two or more drugs, or polypharmacy, is required. Selection of rational combination therapy requires consideration of the clinical antiepileptic or anticonvulsant effects, adverse effects, drug interactions, and relationship between effective and toxic drug levels. Mechanisms of action of each agent must also be studied. Optimal combination therapy often is achieved with drugs that have different mechanisms of action, relatively few adverse effects, high therapeutic indexes, and limited or no drug interactions. The goal of rational polypharmacy is to produce improved seizure control with minimal or no adverse effects.