The cellular response to DNA damage relies on a network of pathways activated upon genotoxic stress, including cell cycle checkpoints, DNA repair, DNA damage tolerance mechanisms, and the activation of innate immune responses. Defects in these processes lead to genomic instability, a fundamental driver of numerous inherited human disorders and age-associated diseases, most notably cancer, where the DNA damage response (DDR) represents an important therapeutic target. This EMBO Workshop will address the diverse sources of genomic instability and the molecular mechanisms that preserve genome integrity, spanning basic research on chromatin organisation to preclinical research using a range of approaches from biochemistry and structural methods to single-cell biology and animal models. It will further explore the links between genome maintenance pathways and human disease, as well as their potential for therapeutic intervention.