This chapter focuses on the pathophysiology of degenerative cervical myelopathy (DCM). It starts by introducing the etiology of DCM, touching on genetic risk factors in humans and animal models and then explains ischemia, blood–spinal cord barrier disruption, and neuroinflammation during chronic compression of the spinal cord. It also focuses on systemic implications, such as the recent connection between DCM and gastrointestinal dysfunction, cytokines, chemokines, and microRNAS as potential biomarkers of DCM progression as well as neurobehavioral recovery following surgical decompression. It ends the chapter highlighting the main animal models used in the basic science to reproduce and study DCM progression and surgical decompression.