The genome is constantly exposed to exogenous DNA damaging events in the form of radiation, viral infection and chemicals. Endogenous processes such as DNA replication and free radical formation also threaten the integrity of the genome. DNA damage is directly deleterious to cells and also promotes tumorigenesis. Eukaryotic organisms have evolved a signaling pathway, called the DNA damage response, to protect against genomic insults. Sensor proteins detect various forms of damage, and convey signals via a complex pathway regulated by protein phosphorylation, stabilization and transcriptional regulation. The DNA damage response causes cell cycle arrest and induction of DNA repair functions, such that cells with modest damage may survive. However, cells with more severe damage are induced to undergo apoptosis. Two compelling studies show that the DNA damage response is activated very early during tumorigenesis, providing evidence that the DNA damage response could function as a barrier in early tumorigenesis. We recently demonstrated that the DNA damage response alerts the immune system by inducing expression of cell surface ligands for the activating immune receptor NKG2D, which is expressed by natural killer cells (NK cells) and some T cells. In this review we discuss the DNA damage response and its link to the innate immune system and tumor surveillance. These findings might have important implications for the understanding of cancer therapies and for drug development.