Introduction: Spreading depression is a transient and self-propagating wave of neuronal and glial depolarization, followed by a temporary loss of brain activities. Spreading depression is known by a huge redistribution of ions between extra- and intracellular spaces and spreads at the velocity of 2-3 mm/min in all directions. Investigations indicate the role of spreading depression in several neurological disorders, including migraine with aura, epilepsy, traumatic brain injuries, transient global amnesia, stroke, and spinal cord diseases. Conclusion: Despite decades of research and hundreds of reports on the mechanism of spreading depression propagation, the exact mechanism of propagation still need to be elucidated. The present study reviews a group of these observations, in order to give some new insights into the complex mechanism of the propagation of spreading depression.