Longitudinal extensive transverse myelitis (LETM) is defined as a spinal cord lesion that extends over three or more vertebrae, as seen on MRI of the spine. The clinical presentation of a patient with LETM is often dramatic and can consist of paraparesis or tetraparesis, sensory disturbances, and gait, bladder, bowel and/or sexual dysfunction. LETM is a characteristic feature of neuromyelitis optica, but such spinal lesions can also occur in various other autoimmune and inflammatory diseases that involve the CNS--such as multiple sclerosis, sarcoidosis or Sjögren syndrome--or in infectious diseases with CNS involvement. Patients with a neoplastic disorder or traumatic spinal cord injury can also present with longitudinal spinal lesions. In this Review, the signs and symptoms that suggest various etiologies and differential diagnoses of LETM are described, and illustrated by educational case studies. The best therapeutic options for patients with each diagnosis are also discussed.