The treatment of epilepsy is complicated by the multiple seizure types and epilepsy syndromes needing therapy. In addition, seizures in up to 30% of epilepsy patients are resistant to available medications. The three newest antiepileptic medications (lacosamide, rufinamide, and vigabatrin) all putatively have novel mechanisms of action, which might increase the chance of treatment success in patients failing previous antiepilepsy drug trials and the chance of successful synergy with currently available medications. In our experience, all three drugs generally are well tolerated, although the risk for serious long-term complications with vigabatrin presents special challenges and precautions. Lacosamide is approved for the adjunctive therapy of complex partial seizures in adults and also is available in an intravenous formulation. Rufinamide is a new treatment option for seizures associated with Lennox-Gastaut syndrome, and although it is not FDA approved for partial seizures, it has shown efficacy for that indication as well. Vigabatrin has been approved in adults for drug-resistant complex partial seizures and in infants as a treatment option for infantile spasms.