A significant proportion of women with epilepsy have an increase in their seizure frequency during pregnancy. Multiple factors may be involved in this phenomenon, but changes in antiepileptic drug (AED) concentration appear to be the most significant. AED concentration declines as pregnancy progresses, due primarily to dynamic changes in plasma protein binding. Total concentrations of all first-line AEDs (carbamazepine, phenytoin, phenobarbital, and valproic acid) fall significantly during pregnancy, compared to baseline. Free or unbound drug concentrations, however, fall significantly only for phenobarbital. Valproate free concentrations actually increase by 25% by delivery. Women taking carbamazepine, phenytoin, or valproate may be relatively protected by adequate free concentrations of these compounds. When managing pregnant women with epilepsy, measurement of free AED concentrations and appropriate dose adjustment to maintain therapeutic ranges will permit more effective clinical management than using total concentration values.