Four prominent causes of pathologic double-strand breaks in living cells are listed. Among multicellular eukaryotes, physiologic double-strand breaks are found only the vertebrate immune system. V(D)J recombination is present in all true vertebrates and is initiated by an endonucleases complex composed of RAG1 and 2 (Lieber et al., 2006). Class switch recombination is present in only a subset of these vertebrates and is initiated by cytidine deaminase called activated-induced deaminase (AID). DSBs that arise in late S or G2 of the cell cycle are often repaired at long regions (> 100 bp) of homology using homologous recombination (though single-strand annealing also can occur) (Sonoda et al., 2006). However, the dominant pathway for the repair of double-strand breaks is called NHEJ, and this repair pathway can function at any time during the cell cycle. NHEJ does not use long stretches of homology, but the processing of the DNA ends can, in a minority of cases, be influenced by alignment of a few nts of homology called terminal microhomology (typically 1 to 4 nt in length). It should be noted that NHEJ proceeds even if there is no terminal microhomology. Important protein components of the repair pathways are listed.