Spreading depression (SD) is a wave of sustained depolarization challenging the energy metabolism of the cells without causing irreversible damage. However, brain injury, especially focal ischemic stroke, triggers SD-like waves, which in the vicinity of the original damage site contribute to enlargement of the dying brain tissue. Brain injury induces expression of several genes, which are thought to play a role in neuronal death, and therefore represent potential targets for therapy. One such gene is cyclooxygenase-2 (COX-2), an inducible prostaglandin and superoxide producing enzyme. Here we review our recent studies on the regulation of COX-2 in SD.