Genome instability due to the loss of DNA repair factors can drive developmental defects, autoinflammatory disease, and cancer. Two major signaling pathways are activated by genome instability—DNA damage checkpoint signaling, leading to p53 activation, and innate immunity, largely driven by the DNA sensor cGAS. Like p53, cGAS is thought to drive cell death and senescence during genotoxic stress in addition to its canonical inflammatory functions, but its role during cellular differentiation and carcinogenesis is poorly understood. Furthermore, it is heavily debated whether the cGAS pathway primarily has tumor-suppressive or oncogenic functions. A study in this issue of Cancer Research used a hematopoietic lineage-specific knockout of the ribonucleotide repair gene Rnaseh2b to introduce genotoxic stress, resulting in severe hematopoiesis defects and increased incidence of hematologic cancers. These two effects were driven by and antagonized by p53, respectively. Surprisingly, despite increased innate immune signaling, the cGAS pathway did not seem to play a role in either process. These findings suggest that innate immune responses to genotoxic stress may be more subtle and context-specific than appreciated, indicating that a more detailed understanding of pathway activation and signaling consequences is needed.