Nijmegen Breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, immunodeficiency, and increased predisposition to the development of malignancy. Due to the overlap of clinical and cellular features of patients with ataxia telangiectasia (AT), NBS was described as an AT variant syndrome until the underlying gene product mutation was identified. Cells from both AT and NBS patients show increased sensitivity to ionizing radiation (IR), genomic instability and cell cycle checkpoint defects following DNA damage, suggesting that both gene products participate in the same DNA damage response pathway. Here we highlight recent developments and refinements in our understanding of the interplay between NBS1 and ATM in vivo.