Reactive oxygen species (ROS) are short-lived, highly reactive molecules that can cause DNA damage and influence the DNA damage response (DDR). ROS are involved in the genotoxic effects of chemotherapeutic agents and ionizing radiation. Recent studies have shown that ROS can modulate the cellular response to DNA damage, particularly in the context of double-strand breaks (DSBs). Clinical trials using ROS modulators in combination with genotoxic therapy have had mixed results, highlighting the need for further research. ROS play a key role in DNA damage induction, including through genotoxic agents and oncogenic replication stress. ROS can also influence the sensing of DSBs by modulating sensor kinases like ATM and ATR. ROS affects the activation of DDR pathways, including the role of chromatin remodelers and the phosphorylation of H2AX, which is crucial for DNA repair. ROS also influence signal transduction within the DDR, affecting checkpoint kinases such as Chk1 and Chk2. ROS can promote cell cycle arrest by modulating the activity of Cdc25 phosphatases and mitotic kinases like PLK1 and Aurora-A. Additionally, ROS regulate p53 function, which is critical for DNA repair and apoptosis. ROS also impact DNA repair processes, although direct effects on repair proteins are not well understood. ROS can contribute to genomic instability and influence the effectiveness of DNA repair pathways, which has clinical implications for cancer treatment. In the context of chemotherapy and radiotherapy, ROS can enhance or reduce the effectiveness of treatment. ROS modulators have been tested in clinical trials with mixed results, and further research is needed to understand their role in cancer therapy. The clinical relevance of ROS in cancer treatment is significant, and further studies are required to explore the mechanisms and potential therapeutic applications of ROS modulation in cancer.Reactive oxygen species (ROS) are short-lived, highly reactive molecules that can cause DNA damage and influence the DNA damage response (DDR). ROS are involved in the genotoxic effects of chemotherapeutic agents and ionizing radiation. Recent studies have shown that ROS can modulate the cellular response to DNA damage, particularly in the context of double-strand breaks (DSBs). Clinical trials using ROS modulators in combination with genotoxic therapy have had mixed results, highlighting the need for further research. ROS play a key role in DNA damage induction, including through genotoxic agents and oncogenic replication stress. ROS can also influence the sensing of DSBs by modulating sensor kinases like ATM and ATR. ROS affects the activation of DDR pathways, including the role of chromatin remodelers and the phosphorylation of H2AX, which is crucial for DNA repair. ROS also influence signal transduction within the DDR, affecting checkpoint kinases such as Chk1 and Chk2. ROS can promote cell cycle arrest by modulating the activity of Cdc25 phosphatases and mitotic kinases like PLK1 and Aurora-A. Additionally, ROS regulate p53 function, which is critical for DNA repair and apoptosis. ROS also impact DNA repair processes, although direct effects on repair proteins are not well understood. ROS can contribute to genomic instability and influence the effectiveness of DNA repair pathways, which has clinical implications for cancer treatment. In the context of chemotherapy and radiotherapy, ROS can enhance or reduce the effectiveness of treatment. ROS modulators have been tested in clinical trials with mixed results, and further research is needed to understand their role in cancer therapy. The clinical relevance of ROS in cancer treatment is significant, and further studies are required to explore the mechanisms and potential therapeutic applications of ROS modulation in cancer.