Maintenance of genome stability depends on the appropriate response to DNA damage. This response is based on complex networks of signaling pathways that activate numerous processes and lead ultimately to damage repair and cellular survival — or apoptosis. The protein kinases ATM and ATR are master controllers of some of these networks, acting either in concert or separately to orchestrate the responses to specific types of DNA damage or stalled replication. Understanding their mode of action is essential to our understanding of how cells cope with genotoxic stress.