Epilepsy is one of the most common chronic neurologic disorders. Despite the plethora of antiepileptic drugs (AEDs) currently available, 30% of patients continue having seizures. This group of patients requires a more aggressive treatment, since monotherapy, the first choice scheme, fails to control seizures. Nevertheless, polytherapy often results in a number of unwanted effects, including neurologic disturbances (somnolence, ataxia, dizziness), psychiatric and behavioral symptoms, and metabolic alteration (osteoporosis, inducement or inhibition of hepatic enzymes, etc.). The need for better tolerated AEDs is even more urgent in this group of patients. Reports have suggested an antiepileptic role of melatonin with a good safety profile.