(1) Background: radiotherapy is a cornerstone of cancer treatment. When delivering a tu- moricidal dose, the risk of severe late toxicities is usually kept below 5% using dose-volume con- straints. However, individual radiation sensitivity (iRS) is responsible (with other technical factors) for unexpected toxicities after exposure to a dose that induces no toxicity in the general population. Diagnosing iRS before radiotherapy could avoid unnecessary toxicities in patients with a grossly normal phenotype. Thus, we reviewed iRS diagnostic data and their impact on decision-making processes and the RT workflow; (2) Methods: following a description of radiation toxicities, we con- ducted a critical review of the current state of the knowledge on individual determinants of cellu- lar/tissue radiation; (3) Results: tremendous advances in technology now allow minimally-invasive genomic, epigenetic and functional testing and a better understanding of iRS. Ongoing large trans- lational studies implement various tests and enriched NTCP models designed to improve the pre- diction of toxicities. iRS testing could better support informed radiotherapy decisions for individu- als with a normal phenotype who experience unusual toxicities. Ethics of medical decisions with an accurate prediction of personalized radiotherapy’s risk/benefits and its health economics impact are at stake; (4) Conclusions: iRS testing represents a critical unmet need to design personalized radio- therapy protocols relying on extended NTCP models integrating iRS