This chapter discusses polytherapy with old and new antiepileptic drugs (AEDs), current clinical experience with drug combinations and future treatment strategies in pharmacoresistant epilepsies. The majority of patients with newly diagnosed epilepsy can apparently be controlled with a single AED. At present, selection of AED combinations is mainly based on personal experience and on a few clinically documented studies. The aim of rational polytherapy is to improve the effectiveness to toxicity ratio: effectiveness should be supra-additive or at least additive and toxicity should be lower than additive. Everyday clinical practice suggests that in some pharmacotherapy-resistant patients, combination of three AEDs has a better effect than two drugs. Drug interactions may produce increases in desired metabolites or decreases in the formation of undesired metabolites. Resistance to pharmacotherapy occurs in a significant number of patients with chronic epilepsy; its pathogenesis and mechanism(s) of development are not fully understood.