Efficient repair of DNA double-strand breaks is essential for the maintenance of chromosomal integrity. In higher eukaryotes, non-homologous end-joining (NHEJ) DNA is the primary pathway that repairs these breaks. NHEJ also functions in developing lymphocytes to repair strand breaks that occur during V(D)J recombination, the site-specific recombination process that provides for the assembly of functional antigen-receptor genes. If V(D)J recombination is impaired, B- and T-lymphocyte development is blocked resulting in severe combined immunodeficiency disease. In the last decade, an intensive research effort has focused on NHEJ resulting in a reasonable understanding of how double-strand breaks are resolved. Six distinct gene products have been identified that function in this pathway (Ku70, Ku86, XRCC4, DNA ligase IV, Artemis, and DNA-PKcs). Three of these comprise one complex, the DNA-dependent protein kinase (DNA-PK). This protein complex is central during NHEJ, because DNA-PK initially recognizes and binds to the damaged DNA and then targets the other repair activities to the site of DNA damage. In this review, we discuss recent developments that have provided insight into how DNA-PK functions, once bound to DNA ends.