The HIV epidemic remains a critical public health priority in the United States. The Ending the HIV Epidemic (EHE) initiative seeks to reduce HIV diagnoses by 75% by 2025 and by 90% by 2030. Certain demographic groups-including transgender women, cisgender Black women, and Black/African American and Hispanic/Latino men who have sex with men-are disproportionately affected by HIV. Pre-exposure prophylaxis (PrEP) has proven effective in reducing HIV transmission. Real-world data indicate that the states with higher PrEP coverage have experienced steeper declines in new HIV diagnoses; however, several barriers hinder equitable PrEP access and uptake. Challenges such as stigma, discrimination, lack of education, and insurance barriers contribute to disparities in PrEP uptake and access to care, particularly in underserved communities. Population health decision-makers, including managed care organizations and federal and state policy makers, can play a vital role in expanding PrEP coverage and uptake by addressing these barriers and ensuring zero out-of-pocket costs for individuals who need PrEP. Enhancing health care provider education and person-centered HIV prevention strategies (eg, same-day PrEP services, telePrEP programs) also can increase PrEP uptake and adherence and patient satisfaction. A continuous focus on improving PrEP access can substantially contribute to achieving the EHE initiative's goal to end the HIV epidemic.