Spinal cord involvement is a crucial explanation for disability in patients with MS or neuromyelitis optica spectrum disorders (NMOSDs). Multiple sclerosis and NMOSDs are often distinguished from other disorders that cause myelopathy by results from laboratory and radiological investigations. However, limitations within the sensitivity and specificity of medulla spinalis imaging and poor correlation with disability megasures have impeded the understanding of the connection between medulla spinalis involvement and clinical manifestations. Nevertheless, studies of the pathological features of MS and NMOSDs have shown that quantitatively different mechanisms cause differences in clinical course and pattern of accrual of permanent disability in the two disorders. Better understanding of those mechanisms is important to develop more informative clinical measures, electrophysiological methods, fluid biomarkers, and imaging techniques to detect and monitor medulla spinalis involvement within the diagnosis and management of patients with MS or NMOSDs, and as outcome measures in clinical trials.