Migraine is among the most common and disabling neurological diseases in the world. Cortical spreading depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache. Experimental models of CSD have been considered highly translational as they recapitulate migraine-related phenomena and have been validated for screening migraine therapeutics. Here we outline the essential components of validated experimental models of CSD and provide a comprehensive review of potential modulators and targets against CSD. We further focus on novel interventions that have been recently shown to suppress CSD susceptibility that may lead to therapeutic targets in migraine.