The response to DNA damage consists of a complex network of cellular pathways that are activated following damage and which includes cell cycle checkpoints, DNA repair, DNA damage tolerance and engagement of innate immunity. Failure to properly respond to DNA damage leads to genomic instability, an underlying cause of various human genetics syndromes and many age-related diseases, such as cancer for which the DDR is an attractive therapeutic target. This EMBO Workshop will cover various aspects of the causes that drive genomic instability as well as the mechanisms ensuring genome maintenance, their link to human diseases and their potential as therapeutic targets.