Control of the COVID-19 pandemic relies heavily on behavioral mitigation strategies such as physical distancing, hand washing and mask wearing. Even with the availability of SARS-CoV-2 vaccines, the extraordinary effort to distribute the vaccines must be paired with continued adherence to behavioral recommendations as well as vaccine confidence. To facilitate rapid and equitable uptake of the vaccines, there is a need for responsive, trustworthy, and evidence-informed communication about vaccination, enhanced trust in science, and engaging populations disproportionately affected by the pandemic. Efforts to address vaccine hesitancy and increase vaccine confidence will address the emerging gaps between vaccine availability and actual vaccination. Although these gaps are attributable, in part, to challenges with logistics and access, social and behavioral drivers of vaccination decision making also have a significant role in vaccination uptake. As federal, state, and local health and public health agencies coordinate vaccine dissemination, there will be a continuous need to adapt to an evolving landscape of SARS-CoV-2 vaccines, new scientific information, and the spread of COVID-19- and vaccine-related misinformation. Facilitating widespread vaccination and maintaining a focus on equity requires thoughtful and compassionate approaches to reach and address the needs of those who are disproportionately affected by the pandemic such as underserved, vulnerable, and racial/ethnic minority populations. This commentary focuses on several National Institutes of Health initiatives that are supporting behavioral and social science research to address SARS-CoV-2 vaccine communication and increase the uptake of vaccination. We conclude with implications for future research.