Pre-exposure prophylaxis (PrEP) is highly effective at preventing HIV acquisition and is a critical tool in the Ending the HIV Epidemic in the U.S. initiative. However, major racial and ethnic disparities across the pre-exposure prophylaxis continuum, secondary to structural inequities and systemic racism, threaten progress. Many barriers, operating at the individual, network, healthcare, and structural levels, impede PrEP access and uptake within Black and Hispanic/Latino communities. This review provides an overview of those barriers and the innovative and collaborative solutions that health departments, healthcare organizations, and community partners have implemented to increase PrEP provision and uptake among disproportionately affected communities. Promising strategies at the individual and network levels focus on increasing patient support throughout the PrEP continuum, positioning and training community members to expand knowledge of and interest in PrEP, and leveraging mobile technologies to support PrEP uptake. Healthcare-level solutions include expanding the venues and types of healthcare professionals that can provide PrEP, and structural- and policy-level options focus on financial assistance programs and health insurance expansion. Key research gaps include demonstrating that pilot studies and interventions remain effective at scale and across varied contexts. Although the last 2 decades have provided effective tools to end the HIV epidemic, realizing this vision for the U.S. will require addressing persistent and pervasive HIV-related disparities in Black and Hispanic/Latino communities. Federal, state, and local partners should expand efforts to address longstanding health and structural inequities and partner with disproportionately affected communities to rapidly expand PrEP scale-up.