The chapter discusses the dynamics and mechanisms of DNA damage and repair, highlighting the initial skepticism about the importance of DNA repair due to its aesthetic appeal as a pristine double helix. However, subsequent research revealed that DNA is subject to continuous damage and that cells have evolved sophisticated mechanisms to respond to such injuries. The early work on DNA damage and repair was influenced by physicists, who introduced concepts from physics to genetics, particularly in understanding the size, mutability, and self-replication of genes. Key discoveries, such as the photoreactivation of UV-induced DNA damage by Albert Kehner and Renato Dulbecco, laid the foundation for understanding DNA repair mechanisms. The chapter also delves into the different types of DNA repair mechanisms, including excision repair (NER, BER, and MMR), which involve the excision of damaged bases and the synthesis of new DNA strands. Additionally, it discusses the repair of double-strand breaks (DSBs) through processes like recombination and non-homologous end joining. The concept of damage tolerance, where cells bypass damaged regions to continue replication, is also explored, along with the role of specialized polymerases in translesion synthesis. The chapter further examines the connection between DNA damage, repair, and cancer, emphasizing the somatic mutation hypothesis, which posits that cancer arises from mutations in genes critical for cell division. It highlights the role of defective DNA repair mechanisms in hereditary cancers, such as xeroderma pigmentosum (XP) and hereditary non-polyposis colon cancer (HNPCC). Finally, the chapter touches on the future of DNA damage research and its implications for understanding and treating diseases.The chapter discusses the dynamics and mechanisms of DNA damage and repair, highlighting the initial skepticism about the importance of DNA repair due to its aesthetic appeal as a pristine double helix. However, subsequent research revealed that DNA is subject to continuous damage and that cells have evolved sophisticated mechanisms to respond to such injuries. The early work on DNA damage and repair was influenced by physicists, who introduced concepts from physics to genetics, particularly in understanding the size, mutability, and self-replication of genes. Key discoveries, such as the photoreactivation of UV-induced DNA damage by Albert Kehner and Renato Dulbecco, laid the foundation for understanding DNA repair mechanisms. The chapter also delves into the different types of DNA repair mechanisms, including excision repair (NER, BER, and MMR), which involve the excision of damaged bases and the synthesis of new DNA strands. Additionally, it discusses the repair of double-strand breaks (DSBs) through processes like recombination and non-homologous end joining. The concept of damage tolerance, where cells bypass damaged regions to continue replication, is also explored, along with the role of specialized polymerases in translesion synthesis. The chapter further examines the connection between DNA damage, repair, and cancer, emphasizing the somatic mutation hypothesis, which posits that cancer arises from mutations in genes critical for cell division. It highlights the role of defective DNA repair mechanisms in hereditary cancers, such as xeroderma pigmentosum (XP) and hereditary non-polyposis colon cancer (HNPCC). Finally, the chapter touches on the future of DNA damage research and its implications for understanding and treating diseases.