 Abstract genomic instability is the hallmark of various cancers, and the accumulation of DNA damage is often observed in these tumors. Radiotherapy and chemotherapy are commonly used treatments for cancer, but they come with side effects such as damage to healthy tissue. Targeted cancer therapies have been developed to specifically target cancer cells without damaging healthy cells, and understanding how DNA damage repair works could help us develop even more effective treatments. We review the history of our understanding of DNA damage repair and its role in cancer, discuss the mechanisms involved in targeted cancer therapies, and outline some of the current clinical trials being conducted. Finally, we propose two hypotheses that could further advance our understanding of how DNA damage repair affects cancer treatment. This article was authored by Rui Xu Ahuang and Pingku Anjou.