In 2013, the number of radiation therapy patients treated with protons reached the milestone of 100,000. Even though this is only a small fraction of radiation therapy patients, proton therapy draws disproportional attention based on assessments of costeffectiveness. The controversy goes beyond attaching a price tag to improved patient care. It is questioned whether protons offer improved outcome at all. The future will see more randomized clinical trials, of which currently only a few are ongoing (eg, prostate and lung). Technological advances improving treatment accuracy or precision (eg, intensity modulated radiation therapy) were often not tested in clinical trials owing to equipoise (1). Further, technology assessments by clinical trials are often hampered by the fact that treatment techniques are constantly evolving. Proton therapy is currently in transition because of the deployment of in-room imaging techniques that are already standard in photon therapy and the move to beam scanning (including intensity modulated proton therapy [IMPT]). At the same time, the advent of lower-cost solutions will expand availability and further proliferate proton usage. Biophysics research contributes to the assessment of proton therapy and mainly focuses on understanding the clinical relevance and on proper utilization of proton beam characteristics. Three aspects are most prominent: (1) understanding doseeresponse relationships to predict treatment outcome; (2) reducing planning and delivery uncertainties; and (3) utilizing the clinical potential of IMPT.