Environmental insults are often detected by multiple sensors that activate diverse signaling pathways and transcriptional regulators, leading to a tailored transcriptional output. To understand how a tailored response is coordinated, we examined the inflammatory response elicited in mouse macrophages by ionizing radiation (IR). RNA-sequencing studies revealed that most radiation-induced genes were strongly dependent on only one of a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, which regulated many IR-response genes, including interferon response genes, via an atypical IRF1-dependent, STING-independent mechanism. Moreover, small, defined sets of genes activated by p53 and NRF2 accounted for the selective response to radiation in comparison to a microbial inducer of inflammation. Our findings reveal that genes comprising an environmental response are activated by defined sensing mechanisms with a high degree of selectivity, and they identify distinct components of the radiation response that might be susceptible to therapeutic perturbation. Display omitted •Most IR-induced genes are dominantly regulated by one of a small number of sensors•IR and ATM activate an IFN response via an IRF1-dependent, STING-independent pathway•The tonic IFN response is activated by STING, DNA-PK, and IRF3, but limited by ATM•NRF2 activated by ROS and p53 largely explain the selectivity of the response to IR Purbey et al. define the transcriptional response to ionizing radiation in macrophages, revealing a strong dependency on a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, the tumor suppressor p53, and the ROS-induced transcription factor NRF2. Their findings point to selectivity in damage-sensing mechanisms, and identify components of the radiation response as potential therapeutic targets.