Research universities are critical contributors to our national research enterprise. They are the principal source of a world-class labor force and fundamental discoveries that enhance our lives and the lives of others around the world. These institutions help to create an educated citizenry capable of making informed and crucial choices as participants in a democratic society. However many are concerned that the unintended cumulative effect of federal regulations undercuts the productivity of the research enterprise and diminishes the return on the federal investment in research. "Optimizing the Nation's Investment in Academic Research" reviews the regulatory framework as it currently exists, considers specific regulations that have placed undue and often unanticipated burdens on the research enterprise, and reassesses the process by which these regulations are created, reviewed, and retired. This review is critical to strengthen the partnership between the federal government and research institutions, to maximize the creation of new knowledge and products, to provide for the effective training and education of the next generation of scholars and workers, and to optimize the return on the federal investment in research for the benefit of the American people. The following are appended: (1) Biographical Information of Committee and Staff; (2) Recommendations Table; (3) Committee Meeting Agendas; (4) Federal Obligations for Science and Engineering to the 100 Universities and Colleges Receiving the Largest Amounts; (5) Federal Research and Development Spending; (6) A Brief Primer on the Paperwork Reduction Act; (7) The Grants Process at the National Science Foundation and the National Institutes of Health; (8) HHS and USDA Select Agents and Toxins--7 CFR Part 331, 9 CFR Part 121, and 42 CFR Part 73; and (9) Report Briefings. [This report was prepared by the Committee on Federal Research Regulations and Reporting Requirements: A New Framework for Research Universities in the 21st Century; Committee on Science, Technology, and Law; Board on Higher Education and Workforce; Policy and Global Affairs; and National Academies of Sciences, Engineering, and Medicine.]