Ligase IV (LIG4) syndrome belongs to the group of hereditary disorders associated with impaired DNA damage response mechanisms. Clinically and morphologically, patients affected with this syndrome are characterized by microcephaly, unusual facial features, growth retardation, developmental delay, skin anomalies and are typically pancytopenic. The disease leads to acute radiosensitivity, immunodeficiency and bone marrow abnormalities. LIG4 syndrome arises from hypomorphic mutations in the LIG4 gene encoding DNA ligase IV; a component of the nonhomologous end-joining machinery, which represents a major mechanism of repair of double strand DNA breaks in mammals. The hypomorphic mutations do not completely abolish but significantly reduce enzyme function. This results in impaired V(D)J recombination, the essential rejoining process in T- and B-cell development, in whose ligase IV plays the key role. As a consequence, patients with LIG4 syndrome frequently develop multiple immune abnormalities, clinically overlapping with severe combined immunodeficiency syndrome.