When the human genome was sequenced, it was surprising to find that it contains approximately 30,000 genes and not 100,000 as most textbooks had predicted. Since then, it became clear that evolution has favored the existence of only a limited number of genes with inducible functions over multiple genes each having specific roles. Many genes products can be modified by post-translational modifications therefore fine-tuning the roles of the corresponding proteins. DNA damage signaling and repair proteins are not an exception to this rule, and they are subject to a wide range of post-translational modifications to orchestrate the DNA damage response. In this review, we will give a comprehensive view of the recent sophisticated mechanisms of DNA damage signal modifications at the nexus of double-strand break DNA damage signaling and repair.