Disclosed herein is a region-based reference management system using in video frame encoding. Source content, such as video game streaming or remote desktop sharing, that includes scene changes or significant instantaneous changes in a region from one frame to the next can present encoding challenges. Techniques disclosed herein use hints about changes in regional frame content, dissect frame content into regions, and associate the dissected regions with stored reference frame data using the hints and information about the regions to more efficiently encode frames.