Neurologic function becomes extremely vulnerable as it funnels through the slender spinal cord and nerve roots. Thus, neoplastic and nonneoplastic processes of the spine and epidural space often give rise to severe backache, radiculopathy, sensorimotor disturbances, loss of sphincter control, and even paraplegia. This clinical scenario, which may suddenly appear, requires an accurate diagnosis that will make possible the proper patient management. Depending on the severity of the symptomatology, the diagnostic approach may be a percutaneous image-guided needle biopsy or an intraoperative consultation in the course of a decompressive laminectomy. In both diagnostic procedures cytologic studies are especially valuable, both for the initial differentiation between inflammation and neoplasia and for the precise identification of the neoplasms found in this region. In this chapter we will consider the cytomorphologic features of the primary and secondary lesions involving the spine and epidural space that threaten the structural and functional integrity of this region of the central nervous system.