The ataxia telangiectasia-mutated (ATM) protein kinase is the master regulator of the DNA double-strand break (DSB) repair pathway. The activation of ATM involves its recruitment to the DSB through interaction with the mre11-rad50-nbs1 complex, followed by the acetylation of ATM by the Tip60 acetyltransferase. This acetylation of ATM within its regulatory domain is essential for activating ATM's kinase activity. Further work has now revealed that Tip60 is activated through direct interaction between Tip60's chromodomain and histone H3 trimethylated on lysine 9 (H3K9me3). The loading of Tip60 onto the chromatin at DSBs therefore represents the primary mechanism for activation of Tip60's acetyltransferase activity in response to DNA damage. The ability of H3K9me3 at DSBs to regulate the activity of Tip60 and the subsequent activation of ATM emphasizes the crucial role played by chromatin architecture in regulating DSB repair. Further, histone methylation and chromatin structure are disrupted in human cancers, implying that altered chromatin structure in tumor cells may impact DSB repair, increasing genomic instability and contributing to the progression of cancer.