DNA damage is typically caused during cell growth by DNA replication stress or exposure to endogenous or external toxins. The accumulation of damaged DNA causes genomic instability, which is the root cause of many serious disorders. Multiple cellular organisms utilize sophisticated signaling pathways against DNA damage, collectively known as DNA damage response (DDR) networks. Innate immune responses are activated following cellular abnormalities, including DNA damage. Interestingly, recent studies have indicated that there is an intimate relationship between the DDR network and innate immune responses. Diverse kinds of cytosolic DNA sensors, such as cGAS and STING, recognize damaged DNA and induce signals related to innate immune responses, which link defective DDR to innate immunity. Moreover, DDR components operate in immune signaling pathways to induce IFNs and/or a cascade of inflammatory cytokines via direct interactions with innate immune modulators. Consistently, defective DDR factors exacerbate the innate immune imbalance, resulting in severe diseases, including autoimmune disorders and tumorigenesis. Here, the latest progress in understanding crosstalk between the DDR network and innate immune responses is reviewed. Notably, the dual function of innate immune modulators in the DDR network may provide novel insights into understanding and developing targeted immunotherapies for DNA damage-related diseases, even carcinomas.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.