Migraine is one of the most prevalent and disabling medical conditions on the planet. Approximately 12% of the world’s population suffers from migraine, while 3% to 5% experience daily or near-daily headaches and other neurological symptoms. Migraine sufferers experience a profoundly diminished quality of life and mental health as well as impaired physical, social, and occupational functioning. While migraine research has been massively underfunded and the disorder clinically dismissed as a “headache,” its genetic and biological basis is increasingly coming into focus as a result of considerable scientific advances. Migraine is considered a largely inherited disorder that is characterized by physiological and structural alterations in the brain that result in paroxysmal episodes of cortical spreading depression, abnormal activation of trigeminovascular nociceptive pathways, and abnormal processing of sensory stimuli. A new era of scientific discovery in the molecular biology and receptor pharmacology of migraine headache has occurred over the past 2 decades and these advances have led to the development of promising new selective compounds and therapies for both the acute and preventive treatment of migraine. This presentation reviews the genetic and pathophysiological basis of migraine and emerging therapies and their physiologic and receptor targets.