ABSTRACT Optical imaging of Cherenkov emission from tissue has recently been demonstrated, providing a mapping related to the radiation delivery to tissue. In external beam radiotherapy, the signal is optimally captured by time-gated intensified cameras, synchronized to the linear accelerator pulses, allowing rejection of the majority of background room light, and providing real time video of each radiotherapy treatment with standard dose rates. This discovery is the first time in history that radiation dose to tissue could be directly imaged with high spatial and temporal resolution. While the imaging technology has inherent limitations to surface regions, it also has the potential for a paradigm change in how radiotherapy is documented and archived for quality audit and real time control. The implementation of Cherenkov imaging is significantly simpler than most dosimetry tools, but needs to be quantitatively accurate to be competitive in the setting of documenting delivered dose. This technology development proposal advances the methods for correction for tissue curvature and tissue optical properties, two of the most dominant factors which alter the linearity between dose and Cherenkov emission. These important corrections are studied in partnership with leading companies that are advancing the methods for patient surface scanning, tissue optical property imaging and Cherenkov imaging system development, ensuring that the discoveries found here will translate into commercial implementation. The studies are tested in the pilot studies of breast cancer patient radiotherapy, in which patients receive up to five daily fractions per week, over 4 to 8 weeks. While radiotherapy delivery incidents occur in less than 1% of treatments, alignment of the patient for daily treatment is a disproportionally high source of errors. As a result, we will explore the applications of Cherenkov imaging in verification of the combined on-patient delivery of the beam, using visible vascular patterns of the breast that appear in the images of the treatment beam. We will also explore the similarity of Cherenkov intensity to thermoluminescent diode measurement, as a solution for verification that is potentially more accurate and easily implemented. Taken together, this project will advance on of the most compelling systems for radiotherapy imaging in decades. The core of the project is combined technology systems, testing the utility in the setting of whole breast irradiation. This technology is embryonic at this point, but its further development could shift the paradigm in what is capable for independent verification of radiation therapy delivery.