Stereotactic body radiation therapy (SBRT) or stereotactic ablative radiotherapy (SABR) is rapidly being adopted as a treatment modality, particularly for liver and lung tumors, and because of the dramatic improvements in tumor control, the use of SBRT is being directed toward other anatomical sites. The success of SBRT has been primarily technology-driven; however, application of fully potent SBRT regimes is now impeded by biological limitations. While the use of SBRT will continue to increase, there are aspects of both normal tissue and tumor response to high dose per fraction radiation exposures that require a further understanding in order to augment the technology gains as well as to minimize the potential harm done by inappropriate application of fully potent SBRT regimes. From a radiobiological perspective, there is a shift in thinking about the models used to extrapolate biological effects at high dose per fraction although the underlying mechanisms are not understood. There are also potential scheduling benefits for SBRT that can be exploited. As such, it may be appropriate to re-examine radioprotective or hypoxic cell cytotoxic agents that were either abandoned or not actively used given their considerable side effects. This may be especially true for hypoxia as the argument can be made on a mechanistic basis that SBRT is inappropriate for use with hypoxic tumors. However, we would challenge that notion. We will discuss these topics from a radiobiological perspective.