The full potential of proton therapy cannot be fully exploited due to uncertainties in the dose deposition characteristics of individual proton treatment beams caused by patient set-up errors, day- to-day changes in patient anatomy, and the overall response of irradiated tissues over the course of treatment. Therefore, current standard proton treatment techniques include the use of larger than desirable treatment margins and safety margins to ensure proper dose is delivered to the tumor in the presence of these uncertainties. The need for these large margins severely limits our ability to exploit the proton Bragg Peak's sharp dose gradients, thus reducing the full clinical potential of proton radiation therapy. Therefore, in order to fully exploit the advantages of the proton Bragg peak, there is a significant and critical need to reduce proton beam range uncertainties, allowing for the reduction of safety margins and the use of more optimal treatment beams, thus allowing the physical advantages of the proton Bragg peak to be exploited. Fortunately, inherent to proton therapy is the emission of elemental `prompt' gamma rays (PG) due to non-elastic proton-nucleus interactions in irradiated tissues. Each element in tissue emits a unique spectrum of PG energies along the path of the beam in the patient, making it a prime signal for beam range verification. We hypothesize that if PG emission during treatment delivery could be adequately measured and imaged, it would allow for the direct verification of the delivered beam range in-vivo. Our long-term goal is to improve the accuracy and precision of proton radiotherapy by monitoring the beam range and tissue response to irradiation in- vivo. To reach this goal, we have established a working academic-industrial partnership dedicated to the translation of our prototype prompt gamma imaging (PGI) system into a clinically viable system. The specific aims of this proposal are to: (1) build an efficient PG detection system, (2) develop a clinical platfor for PG image display and evaluation, and (3) characterize the functionality and perform initial pilot/evaluation studies our PGI system during patient treatment delivery. The proposed research will result in the development of a clinical PGI system for in-vivo imaging during proton radiotherapy treatment delivery. This will allow the measurement of the actual in-vivo dose delivery, thus reducing the inherent uncertainty in proton beam range. By measuring and verifying the beam range, we can reduce or even eliminate the need for large treatment safety margins to account for range uncertainty as a means of ensuring treatment safety and accuracy.