Cortical spreading depression (SD) has been known for more than 70 years. It has been a unique method investigating basic neurophysiology. A growing body of evidence indicates SD is involved in clinical conditions such as migraine with aura, subarachnoid hemorrhage, and traumatic brain injury. In this chapter we describe the application of SD in studying neurovascular and neurometabolic coupling in rat cerebral cortex. Description of the different techniques (electrophysiology, laser-Doppler flowmetry, and oxygen-sensitive electrodes) is followed by in depth step-by-step instructions on how to use them. This chapter will also describe the vascular consequences of SD and how to elicit SD experimentally.