Quality assurance in radiation therapy has been an integral aspect of cooperative group clinical trials since 1970. In early clinical trials data acquisition was non-uniform and inconsistent; computational models for radiation dose calculation varied significantly. Process improvements developed for data acquisition, credentialing, and data management have provided the necessary infrastructure for uniform data. With continued improvement in the technology and delivery of radiation therapy, evaluation processes for target definition, radiation therapy treatment planning and therapy execution undergo constant review. As we move to multi-modality image-based definitions of target volumes for protocols, future clinical trials will require near-real time image analysis and feedback to field investigators. The ability of quality assurance centers to meet these real time challenges with robust electronic interaction platforms for imaging acquisition, review, archiving and quantitative review of volumetric radiation therapy plans will be the primary challenge for future successful clinical trials.