Cortical spreading depression, a slowly propagating wave of transient neuronal and glial depolarization, is widely accepted as the electrophysiologic substrate of migraine aura and a trigger for headache. Recent clinical and experimental evidence reinforces the putative role of cortical spreading depression in migraine pathophysiology. Imaging studies in migraineurs demonstrated hemodynamic changes consistent with cortical spreading depression during aura, whereas recent animal studies helped unravel pathophysiologic aspects such as the triggering mechanisms, genetic and hormonal modulation, and potential therapeutic targets. Here, we provide an overview of recent advances in our understanding of migraine pathophysiology and treatment.