Cortical spreading depolarization (CSD) is an electrophysiologic phenomenon found mostly in the setting of neurologic injury resulting in the disturbance of ion homeostasis and leading to changes in the local vascular response. The bioelectric etiology of CSD shares similarities to those in epileptic disorders, yet the relationship between seizures and CSD is unclear, with several studies observing cortical depression before, during, and after seizure activity, thus obscuring our understanding of whether CSD activity potentiates or limits seizures and vice versa. Cortical sampling has exhibited how the redistribution of ion concentrations in the intra-and extracellular environments interplay between the excitation of seizures and the electrical depression of CSD. Modeling of both environments has suggested that CSD synchronizes the affected tissue, creating a favorable environment for seizure activity; however, other studies have demonstrated the opposite: epileptiform activity initiating waves of CSD. Further studies have underscored the role of the vascular response and subsequent ischemia in CSD that contributes to epileptogenesis. Investigations in migraine, traumatic brain injury, and other neurologic injuries suggest that several drugs may target CSD. Manipulations in the occurrence and nature of CSD can potentially alter the threshold for seizure activity, and perhaps minimize immediate and long-term sequelae associated with epilepsy. (C) 2017 S. Karger AG, Basel