Spontaneous overactivity and abnormal amplification in pain and other, predominantly sensory, pathways in the brainstem, leads to migraine. Current opinion favours a primarily neural cause, involving feedback loops through innervation of cranial arteries in the trigeminovascular system. A relative deficiency of 5-hydroxytriptamine (5-HT) may be near the root cause, and is linked to the action of most drug treatments. Ongoing research is studying the relevance of calcium channel abnormalities, and peptides such as calcitonin gene related peptide, which may be closer than 5-HT to the underlying cause, offering hope for improved treatment in the future. Migraine is usually polygenic. Uncommon migraine variants, such as familial hemiplegic migraine and CADASIL, are single gene disorders. These are neurodegenerative, not primarily headache conditions.