Regulation of the DNA damage response is tightly connected to transcription and replication. These DNA transacting processes share common factors and use similar strategies to exert their function. However, unlike replication and transcription, DNA repair systems may be required anywhere, and at any time, whenever DNA damage occurs in the cell nucleus. This raises questions concerning the spatiotemporal organization of genome caretaking. Currently, quantitative live cell imaging techniques combined with methods to induce local DNA damage in a small region of the nucleus are contributing substantially to unravelling the molecular mechanisms underlying the cellular response to DNA damage.