Local irradiation (IR) is widely used in the treatment of primary and metastatic tumors. However, the impact of IR on the immune response is currently being defined. Local and distant relapse after radiotherapy often occurs. The current rationale for the use of IR is based on direct cytotoxicity to cancer cells; however, recent studies have shown that reduction of tumor burden following ablative (large-dose) IR largely depends on type I IFN signaling and CD8⁺ T-cell response. Here, we review recent findings indicating that antitumor effects of radiation are contributed by both innate and adaptive immune responses. We focus on immune mechanisms, including cytosolic DNA sensing pathways that bridge the traditional view of IR-mediated DNA damage to DNA-sensing immune pathways. Also, we discuss how the efficacy of radiotherapy might be enhanced by targeting nucleic acid–sensing pathways. These findings highlight the mechanisms governing tumor escape from the immune response and the therapeutic potential of synergistic strategies to improve the efficacy of radiotherapy via immunotherapeutic intervention. Clin Cancer Res; 22(1); 20–25. ©2015 AACR.