Migraine is a common, complex brain disorder whose biology is becoming better understood. Despite being the most disabling of the neurological disorders on a worldwide basis, headache disorders broadly, and migraine in particular, have poor research funding and a limited academic base. Given a modicum of investment, new targets, such as calcitonin gene-related peptide–based mechanisms, and entirely novel neuromodulation approaches illustrate that much can be done to improve patient care. Genetics and neuroimaging combined with excellent clinical phenotyping and translational neuroscience approaches are set to transform life for a cohort of patients with these common brain disorders. Ann Neurol 2013;74:423–434