Eukaryotic nuclei are constantly being exposed to factors that break or chemically modify the DNA. Accurate repair of this DNA damage is crucial to prevent DNA mutations and maintain optimal cell function. To overcome the detrimental effects of DNA damage, a multitude of repair pathways has evolved. These pathways need to function properly within the different chromatin domains present in the nucleus. Each of these domains exhibit distinct molecular- and bio-physical characteristics that can influence the response to DNA damage. In particular, chromatin domains highly enriched for repetitive DNA sequences, such as nucleoli, centromeres and pericentromeric heterochromatin require tailored repair mechanisms to safeguard genome stability. Work from the past decades has led to the development of innovative imaging tools as well as inducible DNA damage techniques to gain new insights into the impact of these repetitive chromatin domains on the DNA repair process. Here we summarize these tools with a particular focus on Double-Strand Break (DSB) repair, and discuss the insights gained into our understanding of the influence of chromatin domains on DSB -dynamics and -repair pathway choice.