provide better control of cancer progression via precise delivery of radiation doses to the tumor tissue. New modalities, such as FLASH proton radiotherapy, where high doses are delivered in an ultra-high dose rate fashion, are currently under clinical trials [2; 3]. Importantly, in the last few years, the interest in RT modalities has been renewed due to the ability of RT to promote systemic immune responses that can overcome resistance to immunotherapy. Combinations of RT with immunotherapeutic agents, such as immune checkpoint inhibitors, are increasingly favored for overcoming the barriers and synergizing the efficacy of each intervention alone [4]. While RT effectively targets and destroys cancer cells, it can also result in toxicity and adverse effects at the level of healthy tissues in the vicinity of the irradiated area, as well as at the systemic level. Along with interfering with the basic biological properties of cancer cells (such as growth signal autonomy, unlimited replicative potential, and evasion from growth inhibitory signals along with angiogenesis, invasion, and metastasis), ionizing radiation can often inflict life-threatening damage to normal cells. Common toxicities associated with RT include acute and chronic radiation dermatitis (erythema, dryness, skin desquamation and telangiectasias, fibrosis, and ulceration, respectively), mucositis, fatigue, diarrhea, dysphagia, and radiation-induced fibrosis among others depending on the site of exposure. Cell injury due to IR comprises a spectrum of sequential events and biological processes involving intricate cellular morphologic, molecular, and functional changes that are triggered by IR within minutes to hours after irradiation (early toxicity), related to oxidative stress, DNA damage, and cell death, as well as inflammation and cell proliferation [5]. During the first few minutes after exposure, part of the tumor cell is committed to cell death (apoptosis), while part attempts to repair the damaged DNA by developing a robust stress response. IR-induced cell alterations progress over weeks, months, and even years (late toxicity), leading to late tumor and organ dysfunction (atrophy and fibrosis) and therapy-induced secondary malignancies in some cases. The mechanisms underlying radiotoxicity in human tissues involve increased cell death and inflammation, as well as defective tissue regeneration [6]. Patient radiosensitivity is emerging as a multi-dimensional problem [7; 8], ranging from the microworld of the cell and its environment to the macroworld of patients and their families, including time scale (from minutes to years) and medical physics parameters (dose and RT modalities). The adverse effects exhibit complex patterns across multiple tissues and have unclear boundaries, rather than being a mere and distinct classification to radiosensitive versus radioresistant individuals. The occurrence of radiogenic side effects is a strong limitation of therapeutic radiation, requiring the adjustment of the effective individual dose for the prolongation of the patient's life. Additionally, late effects of RT include radiation-induced secondary malignancies [9]. In view of these clinical complications, cut-offs need to be defined that can guide medical decisions and reliably stratify patients who can tolerate a standardized treatment RT scheme, exhibiting no or mild side effects, from those who show individualized over-sensitivity responses, entailing a combination of adverse effects that counteract therapeutic benefits [10]. The reliable and early prediction of radiosensitivity reactions in the irradiated patient can improve RT planning and optimize RT treatment on a personalized basis. In this review, we summarize the toxicities that are linked with RT and highlight the factors that individualize sensitivity to RT. Given the power of biomarkers in the prediction of patient responses to cancer therapies [11], we particularly focus on molecular biomarkers that can predict radiosensitivity in human patients or human samples.