Multiple sclerosis (MS) and migraine headache coexist in many young female patients. Whether this is coincidental or causally linked remains unclear. The presenting symptoms and signs of MS relapse and migraine aura can be similar and should be differentiated by careful history and examination to ensure proper diagnosis and treatment. White matter lesions on magnetic resonance imaging have specific patterns for each entity and also need to be interpreted carefully. Although a clear link has not been established between migraine and MS, numerous studies have been reported assessing risks, prevalence, and causation. Complicating these assessments are the disease-modifying therapies used to treat MS which have been known to be implicated in causing headache. The recent development of novel treatment options for MS requires practitioners to be aware of polypharmacy and potential drug interactions.