Drug-resistant epilepsy may result from an increased expression of protein transporters in the blood-brain barrier or close to an epileptic focus, negative changes in the structure of inhibitory receptors or ion channels or neurodegeneration. One of the existing therapeutic options is a combined treatment with antiepileptic drugs. It may be suggested that the selection of a proper antiepileptic drug combination should be based upon the preclinical data and first of all consider the drug combinations displaying synergy in a seizure test and antagonism or additivity in neurotoxicity tests. This condition (synergy in convulsive tests and antagonism in neurotoxicity tests) seems o be fulfilled by the following combinations: topiramate + lamotrigine, topiramate + oxcarbazepine or valproate + lamotrigine. Anticonvulsive synergy and neurotoxic additivity show: levetiracetam + carbamazepine (oxcarbazepine) or topiramate and tiagabine+gabapentin. In contrast, an evident antagonism has been found for lamotrigine + carbamazepine (or oxcarbazepine) in a seizure test. Considering experimental data from seizure and neurotoxicity tests may improve the therapy of drug-resistant epilepsy, especially that a combination of lamotrigine + carbamazepine is relatively frequently applied in epileptic patients.