Spreading depression (SD), a transient reversible phenomenon with characteristic ionic, metabolic and hemodynamic changes, has been known for over 55 years. A vast number of studies into this mysterious experimental event provides evidence for SD involvement in brain pathophysiology. There is sufficient evidence to admit that SD plays an important role in some clinical disorders including migraine, cerebrovascular diseases, head injury and transient global amnesia. However, the exact pathophysiological mechanisms of SD are unknown and further studies are needed to demonstrate the involvement of SD in these clinical disorders. The purpose of this review is to collect different evidences and hypotheses which suggest a link between SD and clinical disorders. Learning more about the importance of SD may increase our understanding of SD associated disorders and improve our fundamental research strategies.