The phosphatidylinositol 3-kinase-like kinases (PIKKs) ATM and ATR activate a complex signaling network in response to diverse forms of DNA damage. Initial characterization of these signaling molecules focused on the individual role that each plays in response to specific types of DNA lesions. Recently, a more integrated view of the DNA-damage signaling network has emerged. ATM- and ATR-activated signaling pathways once appeared parallel, but new findings suggest that this cellular circuitry is highly interconnected. Communication between ATM and ATR enables the cell to respond to DNA strand breaks and inhibition of DNA synthesis with coordinated, highly modulated outputs. In this article, we focus on several new developments that give insight into the integrated processing of diverse signals that arise during the damage and replication of DNA.