Since January 2020, more than 7.8 million cases of coronavirus disease 2019 (COVID-19) and 215 000 deaths have occurred in the US. In response to the pandemic, vaccine development has been moving at record speed through strong public or private partnerships, with nearly 200 vaccine candidates in development or in trials. In the US, 8 vaccine candidates have received federal support under Operation Warp Speed, and 4—from Moderna, Pfizer/BioNTech, Oxford/AstraZeneca, and Janssen—have entered phase 3 trials. Vaccines will be critical for the prevention and control of COVID-19 in the US and worldwide, yet these efforts cannot succeed without public confidence in a vaccination program. Demonstrating vaccine efficacy and safety during clinical trials and implementing a robust postlicensure vaccine safety monitoring system as the vaccine is deployed in larger, more diverse populations is central to public confidence and enabling timely and accurate policy decisions for population-level use.