Criteria that were developed for monitoring free (unbound) rather than total (free plus bound) concentrations of antiepileptic drugs include extensive and variable binding to plasma proteins. Phenytoin and valproic acid belong to this category. It is shown that free drug concentration is independent of total drug concentration, whereas total drug concentration depends on free concentration and free fraction. Because antiepileptic drugs are predominantly bound to albumin, free fraction will increase in the presence of hypoalbuminemia (hepatic and renal disease, burns, and pregnancy). Free fraction also increases because of saturable binding (valproic acid) and competitive binding (valproic acid displacing phenytoin). There is suggestive evidence that side effects may be more closely related to the free, rather than to the total, plasma concentration of phenytoin. The clinical evidence that side effects or therapeutic effects are better correlated to the free, rather than the total, concentration of valproic acid or carbamazepine is not yet convincing. Knowledge of the free concentration improves our understanding of therapeutic and toxic effects of low total plasma concentrations. Further clinical trials are necessary for definitive assessment of the clinical relevance for free drug monitoring of valproic acid, carbamazepine, and phenytoin in the management of epileptic patients.