In this mini-review, we present the idea of complex (clustered DNA damage), the signature of IR, by a different perspective that of its clinical implications and its involvement in the route to carcinogenesis. As recently discussed in Pateras et al. , enthralling evidence supports the idea that DNA damage response and repair (DDR/R) and immune response signaling networks work together towards the proper function of organisms and homeostasis. We believe that there is a strong linkage between the induction of complex DNA damage, deficient or incomplete DNA repair, constant DDR/R triggering and the continuous activation of the immune system. This vicious relationship which is usually accompanied by GI can be considered without any doubt as the major pathway leading to carcinogenesis . Chronic inflammation which is synonymous to the activation of innate immune system can lead to the downregulation of DNA repair pathways and cell cycle checkpoints due to the release of inflammatory mediators and ROS which can lead to GI . Towards this direction, Colotta et al. suggested a few years ago, that cancer-related inflammation can promote GI by the various inflammatory mediators, leading to accumulation of random genetic modification in cancer or healthy cells. According to the authors, this cancer-relating inflammation represents the seventh hallmark of cancer  in addition to the six hallmarks suggested initially by Hanahan and Weinberg . The understanding of the mechanisms that repair-resistant DNA damage is processed by the cells will benefit significantly therapeutic applications maximizing tumor killing and minimizing radiation toxicity for the cancer patient under RT.