Repair of DNA double-strand breaks (DSBs) is indispensable for life. Therefore, most living organisms have at least two pathways to repair these breaks: homologous recombination (HR) and nonhomologous end-joining (NHEJ). HR is the main repair mode for replication-associated DSBs, while NHEJ deals with most other breaks, especially during the G0/G1 phase of the cell cycle. Characterization of the core NHEJ machinery over the past 20 years has been accompanied by elucidation of the genetic basis of several types of severe combined immunodeficiency (SCID) and a better understanding of the mechanisms regulating the choice between HR and NHEJ. In this chapter, we will therefore discuss the NHEJ mechanism along with considerations on DSB repair pathway choice and associated disease phenotypes.