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To date, the United States (U.S.) has been the most heavily impacted country by the coronavirus disease 2019 (COVID-19). By November 30, 2020, when this paper was written, 13.5 million cases were reported in the U.S. with over 268 000 deaths. Historically, vaccines have been one of the most effective and efficient technical tools for controlling a communicable disease. While the development of these vaccines has certainly been a challenge, it could be more challenging to achieve robust vaccine uptake because of many barriers. In this review, we focused on two types of barriers documented from long-term experience in the U.S.: structural and attitudinal. Structural barriers are systemic issues that impact one's ability to access a service, and they include time, transportation, cost, and clinic or outlet location; while attitudinal barriers are beliefs or perceptions that impact the willingness of at-risk individuals to seek out and/or accept a service. In the context of vaccination they include beliefs about the communicable disease, beliefs about vaccines, fear, and trust in healthcare and governmental agencies. Of the attitudinal barriers, public trust is a barrier that is of particular importance. In addition to affecting reception of vaccines, it may exacerbate disparities and reduce the likelihood of success of a vaccination program. Recommendations are made to overcome attitudinal barriers to help improve the effectiveness of vaccination programs for COVID-19 control in the U.S., such as building public support through bipartisan endorsements and leveraging social media platforms to promote vaccination.