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Despite advances in radiation oncology, patients still experience adverse events. Little is known on the mechanisms of cellular injury and relative effectiveness of protons in comparison to photon radiation in a variety of normal tissues, which are likely to be exposed during the treatment of different types of cancers. Therefore, during the presentation, I will present the current status of clinical trials and literature that comparing proton vs. photon therapy on normal tissue toxicities. Furthermore, I will discuss pre-clinical data with possible mechanisms underlying observed differences in cells after proton vs. photon radiotherapy. These investigations will lead to identify gaps, opportunities, and novel insights to help better design future clinical trials and experimental studies in proton therapy.