Epilepsy is the tendency to have recurrent, unprovoked seizures. Although 70% of epileptic seizures can be controlled with monotherapy (treatment by single antiepileptic drug), a combination of two or more anti-epileptic drugs (AEDs) may be required to improve efficacy (seizure control) and tolerability. Polytherapy (treatment with two or more AEDs) can affect efficacies and side effects in additive, supra-additive (synergistic) or infra-additive fashion. The effect is considered supraadditive when the efficacy of the combination is greater than the sum of the individual drug efficacies, while it is considered infra-additive when the efficacy of the combination is less than the sum of the individual drug efficacies. Here, we have reviewed the available studies and evidences for the application of polytherapy in humans and animal models, to understand which combination of AEDs act as a synergistic polytherapy for epilepsy. We have searched the bibliographic databases MEDLINE and PubMed for studies conducted from 1950 to 2013 and have concluded that, although promising results from the experimental point of view support the combinations of topiramate separately with lamotrigine, gabapentin and felbamate, the most reliable evidence supports the use of valproate and lamotrigine, as this combination generates encouraging results in animal models. Though effectiveness of this combination is supported by human data, there is the possibility of increased side effects. The new drugs are all effective as add-on therapy; there is some evidence that at present, in clinical practice, levetiracetam and topiramate may be the most effective add-on therapies in partial and some generalized epilepsies.