The pharmacologic treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent severe headaches often require both approaches. Preventive therapy is used to try to reduce the frequency, duration, or severity of attacks. The preventive medications with the best-documented efficacy are amitriptyline, divalproex, topiramate, and the beta-blockers. Choice is made based on a drug’s proven efficacy, the physician’s informed belief about medications not yet evaluated in controlled trials, the drug’s adverse events, the patient’s preferences and headache profile, and the presence or absence of coexisting disorders. Because comorbid medical and psychologic illnesses are prevalent in patients who have migraine, one must consider comorbidity when choosing preventive drugs. Drug therapy may be beneficial for both disorders; however, it is also a potential confounder of optimal treatment of either.