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With over 1.2 million American currently living with HIV, a complex epidemic across this large, diverse country, and a fragmented health care system marked by widening health disparities, the U.S. HIV/AIDS epidemic requires sustained scientific and public health attention. With high incidence densities sustained over decades and an epidemic increasingly concentrated among racial, ethnic, and sexual and gender minority persons and communities, the U.S. epidemic has been stubbornly persistent. This has been true despite extraordinary scientific advances in prevention, treatment and care—advances which have been led to a significant degree by U.S. supported science and researchers. In this watershed year of 2020, and in the face of the COVID-19 pandemic, it is clear the U.S. will not meet the stated goals of our current National HIV/AIDS Strategy, particularly reductions in new infections, decreases in morbidity, and reductions in HIV stigma. The 6 papers in this Lancet HIV in the USA series have each examined the underlying causes of these challenges, and laid out paths forward for an invigorated, sustained, and more equitable response to the U.S. HIV epidemic. The current sciences of HIV surveillance, prevention, treatment, and implementation all suggest that the visionary goals of the Ending the HIV Epidemic Initiative in the US may be achievable—but fundamental barriers and challenges must be addressed, and the research effort sustained, if we are to succeed.