The coronavirus disease 2019 (COVID-19) has had a profound impact on the academic research enterprise. Over the span of just a few weeks in March 2020, most large U.S. research institutions closed the majority of their laboratories, studios, and offices, suspended travel and fieldwork, and paused the majority of human research, resulting in the halt of more than 80% of all on-site research activity (1). After months of limited operations, laboratory-and field-based research in the basic and natural sciences were among the first activities to resume. These activities presented relatively low risk for transmission with implementation of proper control measures such as face coverings, health screens, and social distancing. Performing human research during a global pandemic, however, raises new ethical and practical challenges on a scale never before seen. Across the clinical, social, and behavioral sciences, human research can require close contact between researchers and participants, over variable observational periods, and across a variety of locations (e.g., clinics, schools, prisons). Therefore, research with human participants has been slower to resume given the risks associated with potential direct and/or airborne transmission between and among researchers and participants. Indeed, early evidence suggests that research disciplines that rely on face-to-face human contact are among the disciplines that have seen the steepest drop in productivity during the pandemic (2), despite the fact that human research constitutes a significant fraction of the research enterprise. Not all human research paused as stay-at-home orders were implemented across the United States. Work continued on projects that could be performed remotely, as did critical clinical work to help understand and develop solutions for the ongoing pandemic. Some COVID-19 therapeutic trials with potential immediate, life-saving benefit began with numerous safety precautions (3, 4). Many clinical trials with potential immediate life-saving benefit for a range of conditions continued through the pandemic, Performing human research during a global pandemic raises new ethical and practical challenges on a scale never before seen. To safely and ethically restart more of the human research portfolio, institutions must develop guiding principles and an explicit plan for managing human research during the pandemic.