The chromosomal instability syndromes, Ataxia-telangiectasia (A-T), Fanconi anaemia (FA), Bloom syndrome (BS), and Nijmegen Breakage Syndrome (NBS) have been known as autosomal recessive disorders for many years. More recently, some very rare variants such as Ataxia-telangiectasia-like disorder (ATLD) and RAD50 deficiency have been identified. A-T and NBS are paradigms for the inherited basis of human radiosensitivity. They also share some further clinical aspects, particularly immunodeficiency and a predisposition to lymphoid tumours. A-T and NBS are caused by mutations in the ATM and NBS1 genes, respectively. Fanconi anemia (FA) is characterized by hypersensitivity to DNA interstrand crosslinks and susceptibility to tumor formation. FA can be caused by mutations in eleven different genes, although the majority of mutations are accounted for by FANCA and FANCC. The very rare Bloom syndrome is caused by mutation in a single gene, BLM. An important feature which all of these disorders have in common is that the genes identified are involved in aspects of recombination repair of DNA damage. I will discuss in more detail the signalling and repair mechanisms that are initiated by ATM, the product of the gene mutated in Ataxia-telangiectasia, together with the MRE11/RAD50/NBS1 (MRN) complex. Both ATM and the MRN complex function as cellular sensors to DNA double-strand breaks, which lead to the recruitment and phosphorylation of an array of substrate proteins involved in DNA repair, apoptosis and cell-cycle checkpoints, as well as gene regulation, translation initiation and telomere maintenance. In essence, the identification of the genes underlying chromosomal instability syndromes have greatly expanded our knowledge about basic cellular survival mechanisms as well as about the molecular roads leading to cancer. The mutational spectra of these genes have now been elaborated in several populations which has improved the early diagnosis of the affected patients and the subsequent counselling of their families.