Migraine may be comorbid with several other neurologic and psychiatric conditions, including mood disorders (eg, depression, anxiety, panic disorder), epilepsy, stroke, and essential tremor. Comorbidity presents physicians with opportunities and challenges for both diagnosis and treatment. All diseases must be considered, and therapeutic strategies may need to be modified to avoid potential drug interactions. Comorbidities also may provide clues to the pathophysiologies and any shared mechanisms of the two disorders. Longitudinal studies have demonstrated a bidirectional influence between migraine and major depression, but not between migraine and other severe headache. Migraine is strongly and consistently associated with panic disorder. The risk of migraine in epilepsy is increased particularly in individuals with head trauma, partial seizures, and a positive family history of migraine. The influence is bidirectional. There is also growing evidence of an association between migraine and stroke, particularly among women of childbearing age and individuals who experience migraine with aura. Lastly, a bidirectional association between migraine and essential tremor also exists. These findings suggest that migraine, major depression, epilepsy, and essential tremor share one or more common etiologies. Clinicians should be mindful of them as they design treatment strategies, and also should consider the use of a single pharmacologic agent that is effective for all conditions.