A “rapid-learning health system” was proposed in a 2007 thematic issue of Health Affairs. The system was envisioned as one that uses evidence-based medicine to quickly determine the best possible treatments for patients. It does so by drawing on electronic health records and the power of big data to access large volumes of information from a variety of sources at high speed. The foundation for a rapid-learning health system was laid during 2007–13 by workshops, policy papers, large public investments in databases and research programs, and developing learning systems. Challenges now include implementing a new clinical research system with several hundred million patients, modernizing clinical trials and registries, devising and funding research on national priorities, and analyzing genetic and other factors that influence diseases and responses to treatment. Next steps also should aim to improve comparative effectiveness research; build on investments in health information technology to standardize handling of genetic information and support information exchange through apps and software modules; and develop new tools, data, and information for clinical decision support. Further advances will require commitment, leadership, and public-private and global collaboration.