Migraine, the third most common disease worldwide, is a well-known independent risk factor for subclinical focal deep white matter lesions (WMLs), even in young and otherwise healthy individuals with no cardiovascular risk factors. These WMLs are more commonly seen in migraine patients with transient neurologic symptoms preceding their headaches, the so-called aura, and those with a high attack frequency. The pathophysiology of migraine-related deep white matter hyperintensities remains poorly understood despite their prevalence. Characteristic differences in their distribution compared with those of common periventricular WMLs in the elderly suggest a different underlying mechanism. Both ischemic and inflammatory mechanisms have been proposed, as there is increased cerebral vulnerability to ischemia in migraineurs, whereas there is also evidence of blood-brain barrier disruption with associated release of proinflammatory substances during migraine attacks. An enhanced susceptibility to spreading depolarization, the electrophysiological event underlying migraine, may be the mechanism that causes repetitive episodes of cerebral hypoperfusion and neuroinflammation during migraine attacks. WMLs can negatively affect both physical and cognitive function, underscoring the public health importance of migraine, and suggesting that migraine is an important contributor to neurologic deficits in the general population.