Overall Research Project Description We are developing the next generation of software for automated data collection and processing for cryo-electron microscopy (cryo-EM). Cryo-EM is now a widely established and indispensable method for determining the high-resolution structures of biomedically important molecules. The pioneering software packages Leginon and Appion demonstrated the power of automated data acquisition and real-time processing, and there are now numerous programs for automated data acquisition and real-time processing. Despite advances in automation, data collection and processing still require a good deal of manual involvement of an expert electron microscopist. Building on the foundations of Leginon and Appion, we are developing the next generation software package that we call “Magellon”. Magellon will overcome existing bottlenecks and provide an avenue toward fully automated data acquisition that bypasses need for user input during data collection. Importantly, this software will support the computational infrastructure to enable real-time image processing results to inform on and modify the ongoing data collection regime by learning where to acquire images in regions that will yield the highest resolution structures. Using machine learning and the new industry standard tools for distributed processing, we will develop new fast image assessment routines, and provide an application programming interface to enable the incorporation of extensions and plugins from developers in the community.