During the think-tank meeting in Budapest (October 24th, 2019) on “the most provocative questions to Medical Physics (MP) in Radiation Oncology (RO)”, one of the four selected issues focused on the contribution of MP in modeling biological effects in the era of personalized RO. Several questions were suggested to the speakers/debaters to better orient the discussion: (1) Aren''t even simple models validated on smaller but high quality datasets at least as interesting as the results obtained with the "new toys"? (2) How can MP contribute to model effects of concurrent treatment? (3) Can MP contribute in understanding the migration mechanisms of tumor cells? As for the other debated issues, four experts including out-of-field experts and one radiation oncologist were asked to debate the problems from their point of view. Promises, needs and priorities, suggesting visions and actions aimed to maximize the expected contribution of MP to the field were identified. Here we are summarizing the key points of discussion: 1) Medical physicists have fundamental physics skills to set up mathematical description of biological or clinical problems, combined with ability to simplify complex relations to the extent possible. This makes them uniquely positioned to develop models that describe either population trends or individual behavior of cancer and associated therapies. Medical physicists should focus on developing manageable few-parameters models that robustly capture principal components of the picture, combine heterogeneous (dosimetric, clinical, biological, genomic, quantitative imaging…) information into interpretable and generalizable predictive models. Machine learning models (e.g., AI-based), derived from data (top-down) can be useful, but sufficient level of understanding and extensive validation are needed to give sufficient comfort to use them. 2) Medical physicists have made significant contribution in radiation biology. However, in the modern radiotherapy, many of the treatments are combined with chemotherapies, targeted therapies, or immunotherapies. Therefore, it is important to acquire sufficient knowledge and to connect with appropriate expertise (medical oncologists, imaging experts, pathologists, biologists, immunologists….) to be able to contribute in modeling new challenging issues related to the new paradigms of RT in curing and/or preventing metastatic spread, including the interaction with immune system, tumor evolution and metastases, tumor response, lymphocytes irradiation, toxic effects of combined/personalized treatments. 3) Medical physicists should be directly involved in design, execution and interpretation of clinical trials and pre-clinical experiments. Clinical trials/pre-clinical experiments should target testable hypotheses originating from the models themselves to either prove or disprove them or provide grounds for additional insights that would enable refinements of available models. Medical physicists should also act as facilitators of data gathering/data farming, contributing to building and managing advanced data sharing platforms, also within new approaches such as umbrella protocols and basket trials. 4) In order to maximize medical physics contribution, the education of medical physicists needs to substantially corroborate biology and radiobiology skills to a larger extent than currently captured in medical physics curricula. In addition, medical physicists should acquire sufficient level of data analytics expertise (e.g., biostatistics, big data, artificial intelligence) that can constructively contribute to clinical trial design, execution and analyses. In conclusion, medical physics is expected to relevantly contribute to the new challenges of personalized RO in the current, rapidly changing times. The long successful tradition in modeling normal tissue and tumor response must translate in proactive and reactive actions in facing new issues that require fast adaptation toward multi- and trans-disciplinarity nature of radiation oncology. This process is likely to push more and more medical physicists out of their traditional domains, encountering biology-oriented disciplines and clinical and technical experts outside the strict radiotherapy domain. At the same time, the strong roots of medical physicists in the clinical environment remain an amazing and unique value in supporting the translation from/to biology/pre-clinical to/from clinical applications. In order to respond in the best way to these exciting challenges, medical physicists are required to orient their efforts in adapting/increasing skills and to actively promote new roles and responsibilities.