Double-strand DNA breaks (DSBs) are common in eukaryotic cells and are repaired primarily through two pathways: homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). NHEJ is particularly important for repairing pathologic DSBs, such as those caused by chromosomal translocations, and physiologic DSBs, such as those occurring during V(D)J recombination and class switch recombination. The enzymes involved in NHEJ, including the nuclease, polymerases, and ligase, exhibit remarkable structural tolerance and multifunctionality, allowing them to act iteratively and independently on diverse DNA end configurations. This flexibility is crucial for the repair of a wide range of DSBs, from those caused by oxidative stress and ionizing radiation to those resulting from errors in DNA replication and recombination. The article also discusses the evolution of NHEJ, its mechanisms, and the roles of specific proteins such as Ku, DNA-PKcs, Artemis, XRCC4, and DNA ligase IV. Additionally, it explores the alternative NHEJ pathways, such as ligase 4-independent and Ku-independent joining, and the importance of terminal microhomology in simplifying the protein requirements and outcomes of NHEJ.Double-strand DNA breaks (DSBs) are common in eukaryotic cells and are repaired primarily through two pathways: homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). NHEJ is particularly important for repairing pathologic DSBs, such as those caused by chromosomal translocations, and physiologic DSBs, such as those occurring during V(D)J recombination and class switch recombination. The enzymes involved in NHEJ, including the nuclease, polymerases, and ligase, exhibit remarkable structural tolerance and multifunctionality, allowing them to act iteratively and independently on diverse DNA end configurations. This flexibility is crucial for the repair of a wide range of DSBs, from those caused by oxidative stress and ionizing radiation to those resulting from errors in DNA replication and recombination. The article also discusses the evolution of NHEJ, its mechanisms, and the roles of specific proteins such as Ku, DNA-PKcs, Artemis, XRCC4, and DNA ligase IV. Additionally, it explores the alternative NHEJ pathways, such as ligase 4-independent and Ku-independent joining, and the importance of terminal microhomology in simplifying the protein requirements and outcomes of NHEJ.