Idiosyncratic drug reactions can be defined as those adverse drug effects caused by genetically determined enzymatic abnormalities. For the clinician, however, this definition is too limited, and other rare and unusual adverse reactions to the antiepileptic drugs are discussed, including drug interactions, drug allergies, and organ toxicities, as well as true idiosyncrasies. Responsibility for initial recognition and later diagnosis of these reactions falls heavily upon the clinician. In addition to discussing the more common or serious rare reactions, the epidemiology and general mechanisms underlying the reactions are discussed. Treatment involves drug withdrawal, plus general supportive and specific therapy determined by the type and severity of the individual reaction. If primum non nocere should guide the treatment in general, then secundum non plus nocere should guide the treatment of adverse drug reactions.