Repairing chromosome breaks is essential to cell survival. A major lethal effect of ionizing radiation (IR) damage is the creation of double-strand DNA breaks. Recently, a number of mammalian cell mutants that are sensitive to IR damage have been described, revealing a unique repair pathway. The DNA-dependent protein kinase (DNA-PK) is necessary for double-strand-break repair and lymphoid V(D)J recombination. DNA-PK consists of three subunits: the Ku autoantigen heterodimer and a kinase (DNA-PKCS) that is deficient in mouse scid mutant cells.