In today's era of disruption, arguably no US agency is facing greater challenges than the FDA. The unprecedented demands of the COVID-19 pandemic, the need to engage underserved communities and better recognize social determinants of health, the rise of digital health, the emergence of cell and gene therapies—these are but a few of the trends forcing the FDA to create innovative ways to regulate and oversee medical products. For the FDA to meet its public health mission requires that the agency be more flexible than ever before. Former FDA commissioners will discuss the importance of transparency and trust, the politicization of the agency, lessons learned from COVID-19, and how the agency can stay true to its mission in this age of upheaval.