The issues surrounding generic drug substitution in patients with epilepsy are complex. The substitution of one formulation of an antiepileptic drug (AED) for another is controversial. Well-reasoned and defensible cases can be made both for and against such substitution. Although regulatory agencies require that generic and proprietary drugs have similar pharmacokinetic bioequivalence data, their therapeutic efficacy may not necessarily be identical. The paroxysmal nature of epilepsy, the narrow therapeutic index of some AEDs, the need to individualize therapy to achieve seizure control, and the negative consequences of uncontrolled epilepsy distinguishes epilepsy from other clinical conditions. Epilepsy management with AEDs requires careful dose titration and consistent drug exposure at the optimal level for each patient, which can be altered if a different formulation of the AED is substituted. Unexpected variability in plasma concentrations could occur when a patient who has been receiving one formulation of an AED (generic or brand) receives an alternate formulation. Thus, no substitutions should be made for people with epilepsy without the knowledge and approval of the prescribing physician. Patients should be consulted about the substitution, with all risks and benefits carefully explained.