This chapter discusses the factors influencing antiepileptic drug (AED) responses. It introduces the use of computer simulations based on mechanistic interaction models for designing efficient study protocols and data interpretation. The chapter deals with the assessment of the efficacy of combinations based on pharmacokinetic-pharmacodynamic (PK/PD) modeling of concentration-effect data. Development of new effective AEDs and therapeutic approaches ideally implies elucidation of the basic mechanisms of epileptogenesis and seizure generation and, thereby, identification of the appropriate targets. When evaluating the efficacy of drug combinations, the objectives are simple. Seizure semiology plays an important role in clinical diagnosis, but it is seldom used in pharmacologic studies. Determination of plasma concentrations is of utmost importance when evaluating drug combinations. Present knowledge of experimental animal models proposed for refractory epilepsy indicates that multiple factors contribute to its emergence. Simultaneously aiming drugs at the different targets could be a successful way to treat refractory epilepsy.