The Infectious Diseases Society of America is concerned that excessive regulatory oversight is seriously affecting translational research and quality improvement efforts. Careful studies on the subject of research oversight have documented the adverse effects of regulatory burden on clinical, epidemiological, and health systems research. We identified 5 problem areas. First, the application of the Health Insurance Portability and Accountability Act to research has overburdened institutional review boards (IRBs), confused prospective research participants, and slowed research and increased its cost. Second, local review of multicenter studies delays research and does not improve protocols or consent forms. Third, reporting of off-site adverse events to local IRBs is wasteful of the resources of sponsors, investigators, and local IRBs and does not add to participant safety. Fourth, uncertainties about key terms in the regulations governing pediatric research lead to marked differences in the ways that local IRBs review research involving children. Fifth, the lack of consensus on when IRB review is required for quality improvement efforts is slowing progress in this critical area. Relatively simple steps, which do not require legislation or a change in the Common Rule, could improve regulatory oversight in these problem areas.