The DNA double-strand break (DSB) is the principle cytotoxic lesion for ionizing 
radiation and radio-mimetic chemicals but can also be caused by mechanical 
stress on chromosomes or when a replicative DNA polymerase encounters a DNA 
single-strand break or other type of DNA lesion. DSBs also occur as 
intermediates in various biological events, such as V(D)J recombination in 
developing lymphoid cells. Inaccurate repair or lack of repair of a DSB can lead 
to mutations or to larger-scale genomic instability through the generation of 
dicentric or acentric chromosomal fragments. Such genome changes may have 
tumourigenic potential. In other instances, DSBs can be sufficient to induce 
apoptosis. Because of the threats posed by DSBs, eukaryotic cells have evolved 
complex and highly conserved systems to rapidly and efficiently detect these 
lesions, signal their presence and bring about their repair. Here, I provide an 
overview of these systems, with particular emphasis on the two major pathways of 
DSB repair: non-homologous end-joining and homologous recombination. Inherited 
or acquired defects in these pathways may lead to cancer or to other human 
diseases, and may affect the sensitivity of patients or tumour cells to 
radiotherapy and certain chemotherapies. An increased knowledge of DSB repair 
and of other DNA DSB responses may therefore provide opportunities for 
developing more effective treatments for cancer.