The stability of the genome is constantly under attack from both endogenous and exogenous DNA damaging agents. These agents, as well as naturally occurring processes such as DNA replication and recombination can result in DNA double-strand breaks (DSBs). DSBs are potentially lethal and so eukaryotic cells have evolved an elaborate pathway, the DNA damage response, which detects the damage, recruits proteins to the DSBs, activates checkpoints to stall cell cycle progression and ultimately mediates repair of the damaged DNA. As the DSBs occur in the context of chromatin, execution of this response is partly orchestrated through the modification of the DNA-bound histone proteins. These histone modifications include the addition or removal of various chemical groups or small peptides and function to change the chromatin structure or to attract factors involved in the DNA damage response, and as such, are particularly important in the early stages of the DNA damage response. This review will focus on such modifications, the enzymes responsible and also highlights their importance by reporting known roles for these modifications in genome stability and disease.