Background: Quality improvement and patient safety are high priorities, yet insufficient progress has been made in improvement science. Improvement projects are often focused at microsystem levels, precluding sufficient data for rigorous and generalizable conclusions. Furthermore, advancements in the field are hampered by the lack of a national research agenda with clearly defined priorities to systematically build knowledge. Objectives: The NIH-funded Improvement Science research Network (ISRN) is a national network for improvement and translational science. This has established a national research agenda in improvement science. Methods: Multiple data sources contributed to selection of priorities for the national research agenda. A national web-based survey was conducted with stakeholders in quality and patient safety research (n=560). Environmental scans of existing research priorities in the field were conducted. Using these data, a consensus-building meeting was held with academic and practice scholars and leaders to determine priorities for a national improvement research agenda. Results: Survey respondents were deemed to be representative of the targeted interprofessional group thought to be leaders in improvement science. The expert panel deliberations led to development of a national improvement science research agenda. Priorities are classified in the following topics: coordination and transitions of care, high-performing clinical systems and microsystems, integration of best practices into care, and learning organizations and culture of quality and safety. Conclusions: This represents the first national agenda for the development of improvement science. The ISRN creates collaborative research teams of academicians and clinicians in acute-care settings to conduct improvement studies and uses a unique technology infrastructure (see http://www.improvementscienceresearch.net). The ISRN research agenda will inform the selection of a demonstration project to test the infrastructure for implementing multi-site studies. The results of this multi-site research will advance knowledge translation and ultimately inform policy decisions related to quality improvement.