The COVID-19 pandemic challenged the public health system to respond to an emerging, difficult-to-understand pathogen through demanding behaviors, including staying at home, masking for long periods, and vaccinating multiple times. We discuss key challenges of the pandemic health communication efforts deployed in the United States from 2020 to 2022 and identify research priorities. One priority is communicating about uncertainty in ways that prepare the public for disagreement and likely changes in recommendations as scientific understanding advances: How can changes in understanding and recommendations foster a sense that “science works as intended” rather than “the experts are clueless” and prevent creating a void to be filled by misinformation? A second priority concerns creating a culturally fluent framework for asking people to engage in difficult and novel actions: How can health messages foster the perception that difficulties of behavior change signal that the change is important rather than that the change “is not for people like me?” A third priority entails a shift from communication strategies that focus on knowledge and attitudes to interventions that focus on norms, policy, communication about policy, and channel factors that impair behavior change: How can we move beyond educating and correcting misinformation to achieving desired actions?