Monotherapy implies the use of a single active entity and its advantages are recognized. The inappropriate application of drug combinations has been frequently coupled with inadequate recognition or understanding of epileptic syndromes. Pharmacovigilance is obligatory and must be improved for the study of drug interactions. Many studies suggest that multiple neurotransmitters and subtypes of their receptors are involved in the abnormal neuronal excitability that underlies some models of the epilepsies. Studies designed to test efficacy of drug combinations can be observational or experimental. For many antiepileptic drugs (AEDs), therapeutic serum level ranges are more or less well defined. In rational polypharmacy (RP), it is necessary to correlate serum levels with clinical efficacy since the combined drugs may be more active if the serum levels attained by each one in combination therapy are similar to those attained when the drug is used in monotherapy.