To cope with the threat of genome instability, cells have evolved an intricate network of mechanisms ranging from cell cycle checkpoints to specialized DNA repair pathways, and collectively known as the DNA damage response. These mechanisms are evolutionary conserved from prokaryotes to metazoans; however, tissue- and species-specific divergence has emerged in the course of evolution and contributed to the development of additional layers of complexity. This EMBO Workshop will specifically cover the different aspects of the DNA damage response from the perspective of evolutionary, tissue-, and organ-specific diversity, as well as their impact on human health and disease.