Genetic, biochemical, and cellular studies have uncovered many of the molecular mechanisms underlying the signaling and repair of chromosomal DNA breaks. However, efficient repair of DNA damage is complicated in that genomic DNA is packaged, through histone and nonhistone proteins, into chromatin. The DNA repair machinery has to overcome this physical barrier to gain access to damaged DNA and repair DNA lesions. Posttranslational modifications of chromatin as well as ATP-dependent chromatin remodeling factors help to overcome this barrier and facilitate access to damaged DNA by altering chromatin structure at sites of DNA damage. Here we review and discuss our current knowledge of and recent advances in chromatin changes induced by chromosome breakage in mammalian cells and their implications for genome stability and human disease.