This chapter emphasizes the context in which pharmacokinetic and pharmacodynamic interactions are likely to occur during the treatment of epilepsy in handicapped and mentally retarded patients. The diagnosis of epileptic seizures may be difficult in mentally retarded patients, because they cannot in many cases express themselves and therefore fail to tell about their perceived symptoms. The main groups of reasons for intractability of seizures are related to actions by the physician, to the patient, to the epilepsy itself, and to the drugs. Epilepsy in mental retardation commonly presents with several seizure types, drug resistance, concomitant psychiatric symptoms and syndromes with various enzyme abnormalities, which increase the risk of interactions. The outcome of drug therapy may be difficult to assess in the mentally retarded, for example in patients with infantile spasms. The impact of the newer antiepileptic drugs may consist of a better tolerability with fewer interactions.