The vast majority of nervous system neoplasms occur sporadically. However, most adult and pediatric tumors have a hereditary equivalent. These hereditary forms are an invaluable resource in the identification of genes that may be important for sporadic tumor development. In recent years there has been a tremendous increase in the understanding of the genetic basis of many familial cancer syndromes involving the central nervous system (CNS). Several key genes, important in the development of neoplastic disease, have been identified. These genes typically suppress the tumor phenotype (tumor-suppressor gene), maintain normal cellular function and homeostasis, and regulate cell growth and differentiation. Familial CNS tumors are mostly inherited as autosomal dominant traits and involve germline mutations. A somatic mutation inactivating the second allele subsequently results in neoplastic development. This article reviews several familial tumor syndromes involving the CNS including neurofibromatosis type-1, neurofibromatosis type-2, von Hippel-Lindau disease, tuberous sclerosis complex, Li-Fraumeni syndrome, Cowdens syndrome, Turcots syndrome, Gorlins syndrome, Fanconi anemia and multiple endocrine neoplasia. This review highlights their clinical manifestations, molecular genetics, pathophysiology and current treatment. The importance of these pathways for sporadic brain tumors, and the implications for future therapeutic and interventional therapies, are highlighted.