Frequent, severe and long-lasting migraine attacks require prophylaxis. Established drugs used for the prevention of migraine such as beta-adrenoceptor antagonists (beta-blockers), calcium channel antagonists, antidepressants and others have an unknown mode of action in migraine. Their prophylactic effect in migraine was discovered by chance in clinical practice when these drugs were used for other purposes. Recently, research into the mechanisms of migraine and the progressive recognition that cortical hyperexcitability and an imbalance between neuronal inhibition [mediated by gamma-aminobutyric acid (GABA)] and excitation (mediated by excitatory amino acids) may play an important role in migraine pathophysiology have lead to the identification of potential new agents for the prevention of migraine attacks. This paper reviews the recent literature on these new agents. A search was conducted using MEDLINE from 1998 to November 2001 with the following search terms: migraine, preventive, prophylactic and treatment. Headache textbooks edited in 2000 and 2001 were also used. After analysing the available controlled and uncontrolled clinical studies as well as abstracts, divalproex sodium (valproate semisodium) can be recommended for the prevention of migraine. Lamotrigine may be useful for preventing aura associated with migraine, and topiramate seems a promising option pending trials with more patients, which are currently underway. Riboflavin (which is possibly involved in improving neuronal energy production) appears to be a promising agent, although comparisons with established prophylactic medications are needed. Gabapentin, magnesium, lisinopril and botulinum toxin A have recently been suggested to be effective; however, at present, there are insufficient rigorous and reliable controlled data on these drugs for them to be indicated for such use. Emerging options such as tiagabine, levetiracetam, zonisamide and petasites may all be useful, but controlled data are required to confirm their efficacy. The anti-asthma medication montelukast was found to be effective in an open trial, but ineffective in a recently completed controlled trial. There is an expectation that modern neuroscience will soon provide more efficacious and better tolerated prophylactic medications for migraine.