The International League Against Epilepsy has recently published the first ever global consensus definition of drug-resistant epilepsy. Ezogabine (retigabine) has been approved by the U.S. Food and Drug Administration (and its European counterpart) for adjunctive treatment of partial seizures with or without secondary generalization in adults. It is the first antiepileptic drug that specifically acts by opening potassium channels. With the seemingly unstoppable development of a range of newer antiepileptic drugs over the past 2 decades, the available choice has been substantially widened, and the number of possible drug combinations for the treatment of epilepsy is almost limitless. Developing a framework to use antiepileptic drugs rationally, therefore, has become an issue not only of academic interest but also of practical necessity. In this clinical article, Dr. Patrick Kwan and Dr. Martin Brodie provide an updated overview of the pharmacotherapy of epilepsy in adolescents and adults, with particular reference to the clinical pharmacology of antiepileptic drugs, approaches to treatment, and principles of drug selection.