Use of Monotherapy is acknowledged as the standard anticonvulsant therapy although no more than about 65% of patients become seizure-free with a single antiepileptic drug. Therefore, up to 50% of patients with epilepsy are treated at least intermittently with more than one antiepileptic drug. The percentage of patients achieving complete seizure control with combination therapy after ineffective monotherapy is small. Monotherapy and combination therapy are not always contrary to each other; many anticonvulsants have different modes of action and are effectively a combination therapy in one drug. Combinations of anticonvulsants with differing mechanisms of action are called "rational polypharmacy". A superior efficacy of these combinations over combinations of anticonvulsants with identical or similar mechanisms of action have not been proved by randomised trials. Add-on trials with lacosamide and the combination of lamotrigine and valproic acid, however, suggest a superior tolerability and/or efficacy of combinations with differing mechanisms of action. Treatment with drug combinations should take into account, above all, efficacy and safety, interactions, and costs of each antiepileptic drug as well as comorbidity.