Members of the nuclear factor-kappa B (NF-kappa B) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kappa B signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kappa B activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kappa B signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-kappa B target genes, and rapidly transformed neural stem cells-the cell of origin of ependymoma-to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.