Some tumors of the central and peripheral nervous system may be associated with a cancer predisposition syndrome, either hereditary or occurring de novo. Such a syndrome is usually associated with multiple tumors occurring early in life. Patients with neurofibromatosis type 1 present with multiple neurofibromas, especially of the plexiform type (which may transform into malignant peripheral nerve sheath tumor), and pilocytic astrocytomas of the optic pathways. Neurofibromatosis type 2 patients present with multiple schwannomas (typically bilateral vestibular schwannomas), meningiomas, and ependymomas. Li-Fraumeni syndrome (germline TP53 mutation) is associated with choroid plexus tumors (carcinomas), medulloblastomas, and diffuse astrocytomas. Multiple hemangioblastomas are characteristic of von Hippel-Lindau syndrome while subependymal giant cell astrocytomas are pathognomonic of tuberous sclerosis complex. Dysplastic cerebellar gangliocytomas of adult patients occur in Cowden syndrome. Turcot syndrome overlaps with constitutional mismatch repair deficiency syndrome (CMMRD), which is associated with giant cell glioblastomas. Rhabdoid tumor predisposition syndrome (germline mutation of SMARCB1/INI1) is associated with atypical teratoid/rhabdoid tumors. Tumors arising in the setting of a cancer predisposition syndrome develop along specific genetic pathways. Some histopathological and immunohistochemical characteristics of these tumors may point toward such a syndrome. The diagnosis of a cancer predisposition syndrome is of tremendous importance to the patients and their families who require genetic counseling and long-term follow-up. Copyright © 2020. Published by Elsevier Masson SAS.