Growing evidence indicates that spreading depression (SD) may not only relate to some diseases, including cerebral ischemia, migraine, epilepsy, traumatic brain injury and so on, but also affect the physiological courses such as sleep patterns and general arousal. In this paper we review the relationship between SD and cerebral ischemia. The following questions are discussed: (1) The discovery of SD and its brief research history; (2) SD in the intact brain; (3) Peri-infarct SD in focal cerebral infarction. It is suggested that peri-infarct SD contributes to the growth of focal ischemic lesions, and the suppression of SD may become a novel, even a key therapeutic approach for minimizing infarct volume and protecting ischemic neurons after focal cerebral ischemia.