Genome stability is safeguarded by a finely orchestrated cascade of events that collectively represent the DNA damage response (DDR). In eukaryotes, the DDR operates within the dynamic chromatin landscape, where the interplay between DNA repair factors, chromatin remodeling, replication, transcription, spatial genome organization, and cytoskeletal forces is tightly coordinated. High-resolution studies have unveiled chromatin alterations spanning multiple scales, from localized kilobase-level changes to megabase-scale reorganization, which impact chromatin’s physical properties and enhance the mobility of damaged regions. Leveraging this knowledge could pave the way for innovative therapeutic strategies, particularly in targeting chromatin dynamics to destabilize cancer cells selectively. This review, focusing on DNA double-strand breaks (DSBs), sheds light on how chromatin undergoes dynamic modifications in response to damage and how these changes influence the DDR at both local and global levels, offering a glimpse into how nuclear architecture contributes to the delicate balance between genome stability and adaptability and highlighting the importance of exploring these interactions in the context of cancer therapy.