Gliomatosis cerebri (GC) is a neuroepithelial neoplasm with extensive infiltration of large parts of the brain. Recent data showing the involvement of TP53 mutation or nuclear protein accumulation in some cases have linked the astrocytic phenotype of the tumor cells to TP53 alterations frequently found in common astrocytomas. However, the frequency of these alterations is low, and other molecular genetic changes have been only rarely identified. Those found in common high-grade astrocytomas and glioblastomas are usually missing in GC. The distribution of TP53 point mutations, as well as non-coding polymorphic markers and some cytogenetic data, support a monoclonal origin in some cases, and are at least compatible with it in most cases, while no conclusive data suggesting a polyclonal origin have been reported. This raises the question of mechanisms responsible for the enhanced infiltrative potential of the tumor cells in this disease, which have not yet been identified.