During infection, viruses attempt to hijack the cell while the host responds with various defense systems. Traditional defenses include the interferon response and apoptosis, but recent work suggests that this antiviral arsenal also includes the cellular DNA damage response machinery. The observation of interactions between viruses and cellular DNA repair proteins has not only uncovered new complexities of the virus–host interaction but is also reinforcing the view that viruses can reveal key regulators of cellular pathways through the proteins they target.