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Pain, including headache, is a frequent complaint of individuals with multiple sclerosis (MS). Prevalence of headache in patients with MS was reported to be higher than 50%, but it is uncertain if this is different than what is seen in the general population. Nonetheless, it is possible that MS and headaches are comorbid. Case reports illustrated that isolated MS lesions (eg, in "strategic" regions like the midbrain) may cause severe headaches often resembling migraine. Furthermore, the role of MS disease-modifying agents needs to be taken into consideration. Mode of action and side effect profiles differ, and treatment per se may sometimes trigger headache in patients with MS. Thorough evaluation of headache in patients with MS is crucial to optimize patient management to help improve quality of life.