Based on the available experimental data, the etiology of the normal tissue sparing “FLASH effect” at ultra-high dose rate (UHDR) continues to confound explanation, however it’s presence is now without question one of the most fascinating and potentially meaningful topics of radiation biology. The effect has been primarily documented in semi-acute and moderate late effect rodent normal tissue response assays, with differential effects appearing in weeks to months after irradiation. Given the long-timeline of days to weeks in the biological effect, classic radiation biology principles would suggest that DNA damage and/or repair differences must occur between UHDR and conventional dose rate in tissue. Because there appears to be no difference in the tumor control response for UHDR and conventional RT, at the same total dose, the challenge and interest grows even greater and raises major questions about dose energy, dose rate, beam parameters/structure, field/volume effect and damage/repair pathophysiology. The role of oxygen (oxygen enhancement ratio/ OER) continues to be one of most dominant factors in the radiation-induced cytotoxicity of tumors and normal tissues. In the case of UHDR treatment, oxygen measurements have shown that there is not likely depletion to the point of radiobiological hypoxia, but that there are acute reductions in oxygen from the radiolytic induced consumption. The total consumption is very quantifiable in vivo with phosphorescence quenching measurements, are reasonably consistent between electrons and protons irradiation, approximately 0.1-0.2 mmHg per Gray delivered. Additionally, these consumption rates are likely 2X lower in tumor tissue than in normal tissue. The overall consumption rate appears to scale with initial oxygen level. The oxygen consumption is presumably resulting from peroxyl radicals formation when molecular oxygen becomes incorporated in biological macromolecules forming peroxides, which is known radiobiologically as ‘fixation’ of damage because the DNA damage is less repairable. Our measurements have revealed oxygen consumption by FLASH, and hence that presumably the related tissue damage decreases with tissue oxygenation. This effect is lower in tumor tissue as compared to normal tissue, presumably because the former are less oxygenated. The difference between tumor and normal tissue responses likely partly originates from the differences in oxygenation, but also from differences in the microenvironmental composition of the cells and interstitial components as well as differences in biological responses to damage. The available in vivo data and supporting in vitro data will be summarized, and future directions suggested to unravel the link between the in vivo radiochemistry and radiobiology and FLASH-induced damage