The ongoing coronavirus disease 2019 (COVID-19) pandemic has revealed the extreme vulnerability of residents of our nation's more than 15,000 nursing homes. Fewer than 1% of America's population reside in nursing homes, but as reported by the COVID-19 Tracking Project, “this tiny fraction of the country accounts for 35% of U.S. COVID-19 deaths.” Moreover, COVID-19 has disproportionately affected nursing homes with a higher proportion of Black and Hispanic residents. Despite these sobering statistics, the U.S. clinical research enterprise has largely ignored the nursing home population in conducting clinical research on COVID-19. Of the 1.3 million residents of U.S. nursing homes, only a few hundred have participated in randomized controlled trials relating to COVID-19. And while nursing home residents were prioritized for vaccination in the initial COVID-19 allocation phase in the United States, this population was effectively excluded from the pivotal clinical trials of vaccines assessing efficacy and safety. The dire need for scientific evidence to address the escalating crisis in nursing homes became apparent nearly immediately following the onset of the pandemic. Infection prevention and control strategies, therapeutics, vaccine safety and efficacy, and vaccine rollout efforts all would have benefited from rigorous research-based approaches. However, such efforts were impossible not only due to the chaos and lockdowns of nursing homes that occurred with the rapid spread of the virus, but because of circumstances in nursing homes that have existed for decades. In this Commentary, we describe issues that have challenged the conduct of clinical research in nursing homes before and during the pandemic, and which will continue to challenge such efforts into the future.