Radiation therapy is an essential component of cancer care and over 14 million people a year, which is 50% – 60% of total cancer patients. The capabilities available for clinicians to localize and deliver precise amounts of radiation to specific anatomies have improved dramatically over recent years, due to advances in imaging guidance, treatment planning and dose delivery technologies. However, we are now facing a long-lasting bottleneck to further improve the therapeutic ratio, i.e. tumor control vs. normal tissue toxicity. Recent advances in ultra-high dose radiotherapy, abbreviated as FLASH, have shown the potential for reduction in healthy tissue damage while preserving tumor control. FLASH therapy relies on very high dose rate of > 40Gy/sec with sub-second temporal beam modulation, taking a seemingly opposite direction from the conventional paradigm of fractionated therapy. With this, FLASH brings unique challenges to its dosimetry. While spatial dose conformity delivered to a target volume has been pushed to its practical limits with advanced treatment planning and delivery, FLASH RT necessitates novel spatiotemporal dosimetry techniques. The FLASH effect has been reported mainly based upon phenomenological observations with tissue function assays, rather than mechanistic in situ measurements. There are several radiobiological hypotheses around the mechanisms for less damage, however to date none are directly proven, and indeed the data supporting any mechanism is glaringly absent. The central feature dominating most proposed mechanisms is linked to the fact that oxygen depletion, which is expected to occur rapidly at FLASH dose rates, via oxygen radical production with consumption from oxidation reactions.