The Tip60 histone acetyltransferase is part of an evolutionarily conserved multisubunit complex, NuA4, which is recruited by many transcription factors to their target promoters, where it is thought to participate in histone acetylation and transcriptional activation. These transcription factors include tumor promoters and also tumor suppressors, such as p53, which links Tip60 to DNA damage responses. Tip60 also has transcription-independent roles in DNA damage responses. First, independently from NuA4, Tip60 binds the kinases ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and participates in their activation by DNA double-strand breaks. Second, NuA4 is recruited to the chromatin surrounding the breaks and, through a series of chromatin modifications, contributes to the dynamics of DNA repair. These molecular activities might endow Tip60 with multiple and potentially antagonistic biological functions.