Migraine therapeutics are pharmacological, including acute and preventive, nonpharmacological and/or both. Preventive pharmacological strategies serendipitously were discovered to be effective and include drugs from various pharmacological classes (e.g., β-adrenergic blocker, anticonvulsant, tricyclic antidepressants, serotonin receptor antagonist). Converging level I evidence and clinical experience support the use of the antidepressant amitriptyline, the anticonvulsants divalproex and topiramate, and the β-adrenergic blockers propranolol, timolol, and metoprolol in migraine prevention. Other options for migraine prophylaxis exist, but the level of evidence in support of their use is not as robust. All of these drugs have varying degrees of adverse effects, some of which can limit their use. Balancing potential efficacy with risk of adverse effects, addressing patients' expectations and desires, complying with management recommendations, adequate follow up, and accurate assessment of treatment goals are key to migraine prevention. Finally, future migraine-preventive drugs likely will target migraine mechanisms more specifically, which undoubtedly will enhance the therapeutic index.