There have been many experimental studies dealing with combinations of conventional antiepileptic drugs. In the early 1980s, intensive experimental studies were initiated on the possible anticonvulsant activity of ionotropic glutamate receptor antagonists. Although many calcium channel inhibitors actually potentiated the anticonvulsant activity of conventional antiepileptic drugs, in many cases significant side effects were evident. Experimental data may provide a good background for the add-on treatment of epilepsy. Experimental studies provide evidence that a combination of two antiepileptic drugs may produce antagonistic, additive, and supra-additive (synergistic) anticonvulsant effects. A drug combination producing a supra-additive seizure protection should be of clinical interest. Existing experimental evidence points to a favorable synergistic interaction between valproate and phenytoin or topiramate and carbamazepine, or felbamate and all major antiepileptic drugs. The experimental data may be helpful for choosing drug combinations potentially beneficial in epileptic patients.