This chapter addresses the clinical impact of pharmacodynamic (PD) interactions of antiepileptic drugs (AEDs) and the strategies that have been used to discover these interactions. It outlines trials that have provided, or have attempted to provide, relevant data on PD interactions that impact on efficacy. The most common studies of additive effects of AEDs are the randomized placebo-controlled add-on studies of the new AEDs. Negative-PD interactions, also called supra-additivity for side effects, may occur when two drugs with similar side-effect profiles exceed the threshold for that side effect in combination but not individually. Several studies of specific AED combinations have demonstrated an increase in side effects. PD interactions may also increase the likelihood of non-dose-related side effects and serious idiosyncratic reactions. To date, the best data for a potentially supra-additive effect on efficacy are for the combination of lamotrigine and valproate (VPA).