The article discusses the role of ATM and ATR kinases in the DNA damage response (DDR) pathway, which is crucial for maintaining genomic stability in eukaryotic cells. Both kinases are activated by DNA damage and DNA replication stress, but they have distinct DNA-damage specificities and functions. ATM is primarily activated by double-stranded DNA breaks (DSBs), while ATR responds to a broader spectrum of DNA damage, including DSBs and lesions that interfere with replication. The authors highlight the structural outlines of ATM and ATR, emphasizing their HEAT repeats, FAT and FATC domains, and regulatory domains. They also detail how ATM and ATR are activated by DNA damage, with ATM being activated by the Mre11-Rad50-Nbs1 (MRN) complex and ATR being recruited to sites of DNA damage through RPA-coated ssDNA. The article further explains the chromatin-mediated recognition of DSBs by ATM and the activation of ATR through a fail-safe, multistep process involving TopBP1 and other proteins. Finally, it discusses the cross-talk between ATM and ATR, including their influence on each other's localization, direct phosphorylation, and functional redundancy. The authors conclude by emphasizing the importance of understanding the DDR for cancer therapy and the potential of specific inhibitors of ATM and ATR in targeting cancer cells.The article discusses the role of ATM and ATR kinases in the DNA damage response (DDR) pathway, which is crucial for maintaining genomic stability in eukaryotic cells. Both kinases are activated by DNA damage and DNA replication stress, but they have distinct DNA-damage specificities and functions. ATM is primarily activated by double-stranded DNA breaks (DSBs), while ATR responds to a broader spectrum of DNA damage, including DSBs and lesions that interfere with replication. The authors highlight the structural outlines of ATM and ATR, emphasizing their HEAT repeats, FAT and FATC domains, and regulatory domains. They also detail how ATM and ATR are activated by DNA damage, with ATM being activated by the Mre11-Rad50-Nbs1 (MRN) complex and ATR being recruited to sites of DNA damage through RPA-coated ssDNA. The article further explains the chromatin-mediated recognition of DSBs by ATM and the activation of ATR through a fail-safe, multistep process involving TopBP1 and other proteins. Finally, it discusses the cross-talk between ATM and ATR, including their influence on each other's localization, direct phosphorylation, and functional redundancy. The authors conclude by emphasizing the importance of understanding the DDR for cancer therapy and the potential of specific inhibitors of ATM and ATR in targeting cancer cells.