Monotherapy (administration of a single drug) for the treatment of epilepsy has been the gold standard for almost two decades, although exceptions to this rule are still accepted in selected forms of epilepsy. Before this contemporary approach, other attitudes prevailed. The first effective antiepileptic drugs (AEDs), e.g., bromides and, much later, phcnobarbital (PB), were administered in association with central nervous system stimulants to counterbalance sedative effects. Phenytoin was the first effective nonsedative AED and was often administered together with phenobarbitai at moderate dosages to avoid the toxicity associated with a higher dosage of a single AED. PB was also co-administered with ethosuximide in the treatment of absence epilepsy, to prevent the occurrence of both absence seizures and generalized tonic-clonic seizures. Although the practice of monotherapy has become increasingly prevalent, the recent availability of new AEDs has created new problems. In fact, because of the introduction of these AEDs as effective add-on therapy, the use of “rational polypharmacy” was reinvented. From a historical perspective, however, the trend toward simple, cost-effective management of seizures with a single AED is still a goal.