The past decades have brought many advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs, many patients have seizures that do not respond to drug therapy or have related side effects that preclude continued use. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not seem to affect the progression or underlying natural history of epilepsy. Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g., after head trauma or stroke. Thus, there are at least three important goals for the future: (1) better understanding of processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (2) development of disease-modifying therapies, interfering with progression of epilepsy, and (3) improved understanding of neurobiological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of drug resistance. The Second Workshop on New Horizons in the Development of Antiepileptic Drugs explored these three goals for improved epilepsy therapy, with a focus on the search for new drug targets for prevention of epilepsy, for interfering with progression of epilepsy, and for interfering with drug resistance in epilepsy. A special topic dealt with gene expression analysis for target identification. Furthermore, pharmacological and non-pharmacological targets for curing epilepsy were explored. In this conference review, the current status of antiepileptic therapies is critically assessed, and innovative approaches for future therapies are highlighted.