Migraineurs may continue to experience attacks, despite daily use of one or more agents from a wide range of drugs, including β-blockers, calcium channel blockers, serotonin antagonists, tricyclic antidepressants, monoamine oxidase inhibitors, and antiepileptic agents. Divalproex sodium is the only antiepileptic drug approved for migraine prevention. Gabapentin, topiramate, and other antiepileptic agents are being evaluated for migraine prevention and treatment. Prospective, double-blind, placebo-controlled clinical trials of divalproex, gabapentin, and topiramate for migraine prevention generally were composed of a prospective baseline period, a dose titration period, and a fixed-dose treatment period. The primary efficacy variable was a reduction in the 28-day frequency of migraine headache. Patients receiving divalproex for 12 weeks at doses up to 1500 mg/day achieved significant decreases in the migraine frequency (P<.05), corresponding to reductions of 30% to 40% compared with baseline. Nearly half of the divalproex-treated patients had a 50% or more reduction from baseline in headache frequencies (P.05). Asthenia, vomiting, somnolence, tremor, and alopecia were common adverse events associated with divalproex. Significant reductions in migraine frequency were also observed with gabapentin (1800 to 2400 mg/day) when compared with placebo (P<.01), and nearly half of all patients treated at the highest dose experienced a reduction in headache rate of 50% or more. Somnolence was the most commonly reported adverse event among the gabapentin-treated patients. Two single-center, double-blind, placebo-controlled clinical trials evaluated topiramate for migraine prevention. A lower 28-day migraine frequency was seen during 18 weeks of administration at a maximum daily dose of 200 mg (P = .09). In a second study, a significantly lower mean 28-day migraine frequency was observed during 16 weeks of treatment with topiramate (P = .0015). Mean reduction in migraine frequency was also significantly greater in topiramate-treated patients (P = .0037). Paresthesias, diarrhea, somnolence, and altered taste were commonly reported adverse events in the topiramate-treated patients. Unlike some patients given divalproex or gabapentin, some given topiramate reported weight loss. Large, double-blind, placebo-controlled trials may prove the effectiveness of novel antiepileptic drugs in migraine prevention.