Proton therapy has arisen over the past 2 decades with indications grown beyond pediatric, prostate, spine, and ocular tumors. Calls have been growing for high-level evidence to demonstrate the clinical benefit to support its use given its higher cost. This article examined the current status of proton therapy clinical research providing details of completed and ongoing randomized control trials comparing protons and photons, as well as in-depth discussions on challenges and barriers for conducting randomized control trials.