The DNA Damage Response (DDR) is a complex signal transduction pathway that enables cells to sense and respond to DNA damage, ensuring genomic integrity. This review focuses on how the DDR controls DNA repair and the phenotypic consequences of defects in these regulatory functions in mammals. The DDR is primarily mediated by proteins of the phosphatidylinositol 3-kinase-like protein kinases (PIKKs) family, such as ATM, ATR, and DNA-PK, and members of the poly(ADP)ribose polymerase (PARP) family. These proteins sense and respond to various types of DNA damage, including single-strand breaks (SSBs) and double-strand breaks (DSBs), by recruiting and activating a variety of repair factors. The DDR regulates multiple physiological processes, including apoptosis, differentiation, immune surveillance, and DNA repair itself. Defects in the DDR can lead to genomic instability and various diseases, such as cancer. The review also discusses the spatiotemporal regulation of DNA repair, the recruitment of repair factors, and the coordination of repair pathways to ensure accurate and efficient DNA repair. Additionally, it highlights the role of specific proteins and pathways, such as the Fanconi anemia pathway for interstrand crosslink repair and the dNTP biosynthesis pathway, in maintaining genomic stability.The DNA Damage Response (DDR) is a complex signal transduction pathway that enables cells to sense and respond to DNA damage, ensuring genomic integrity. This review focuses on how the DDR controls DNA repair and the phenotypic consequences of defects in these regulatory functions in mammals. The DDR is primarily mediated by proteins of the phosphatidylinositol 3-kinase-like protein kinases (PIKKs) family, such as ATM, ATR, and DNA-PK, and members of the poly(ADP)ribose polymerase (PARP) family. These proteins sense and respond to various types of DNA damage, including single-strand breaks (SSBs) and double-strand breaks (DSBs), by recruiting and activating a variety of repair factors. The DDR regulates multiple physiological processes, including apoptosis, differentiation, immune surveillance, and DNA repair itself. Defects in the DDR can lead to genomic instability and various diseases, such as cancer. The review also discusses the spatiotemporal regulation of DNA repair, the recruitment of repair factors, and the coordination of repair pathways to ensure accurate and efficient DNA repair. Additionally, it highlights the role of specific proteins and pathways, such as the Fanconi anemia pathway for interstrand crosslink repair and the dNTP biosynthesis pathway, in maintaining genomic stability.