This article focuses on clinically relevant teaching points in spinal anatomy and localizing the lesion in myelopathy. The principles underlying spinal cord lesion localization are well established, but improvements in MRI and the discovery of pathologic antibodies associated with causes of transverse myelitis distinct from multiple sclerosis, such as aquaporin-4 IgG and myelin oligodendrocyte glycoprotein IgG, have assisted in diagnosis. The spinal cord has a highly organized neuroanatomy of ascending and descending tracts that convey sensory, motor, and autonomic information. Using integration of clues from the patient's history and neurologic examination, the effective clinician can distinguish spinal cord from peripheral nerve or brain pathology, often determine the level and parts of the spinal cord affected by a lesion, and focus on a likely diagnosis. The advent of MRI of the spine has revolutionized investigation of spinal cord disorders, but an important place for strong clinical acumen still exists in assessing the patient with a myelopathy.