Enabled by increasingly conformal therapy delivery technologies, hypofractionation has become an innovative paradigm of advanced radiation oncology through radiosurgery, stereotactic radiotherapy and high-dose-rate brachytherapy techniques in many cancers, such as lung, CNS, GI, prostate, gynecologic cancers, oligometastases and many others. Radiobiological modeling is central to the design of effective fractionation schemes and to guide dose prescription to the both the tumor target and normal tissue constraints in hypofractionated radiation therapy. For hypofractionated regimens, dose-response data from conventionally fractionated therapy, where ample dose-effect correlation is available, must be extrapolated to the new high-dose domain of ablative radiation. Multiple radiobiological dose response models exist, all of which have advantages and limitations. The Linear-Quadratic (LQ) model has been most widely used to describe cell-kill across variable fractionation schemes. More recent models have been developed to specifically address modeling the novel high-dose fraction domain: the Target and Multi-target Models, Universal Survival Curve Model (Reference 1 above), and the most recently described Generalized Linear Quadratic model (reference 2). Many questions remain: What is the best model? How do models relate to the accumulating clinical SRS and SBRT evidence? How does modeling relate to physics aspects/dose volume parameters? How is modeling best applied in the clinic? This panel will bring together radiobiologists, physicists and radiation oncologists to provide a broad perspective of response modeling for hypofractionated radiation in the wider context of the radiobiology, physics and with strong focus on practical clinical application. Rationale for modeling and the various models and applications to clinical patients will be presented. Gaps in knowledge will be discussed. Innovative approaches to dose response modeling and design of individualized dose schedules for specific diseases will be addressed. At the conclusion of this activity, the learner will be able to do the following: 1. Explain the challenges of dose selection in hypofractionated radiation with respect to tumor control and normal tissue toxicity. 2. Identify the various dose response models and their clinical impact. 3. Explain correlations of the experimental models to clinical patient care.