In sub-Saharan Africa, adolescent girls and young women (AGYW) are 5 to 14 times more likely to be infected with HIV than their male peers. Every day, more than 750 AGYW are infected with HIV. Many factors make girls and young women particularly vulnerable to HIV, including gender-based violence, exclusion from economic opportunities, and a lack of access to secondary school. The President’s Emergency Plan for AIDS Relief (PEPFAR) is dedicating significant resources through the Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe (DREAMS) partnership to impact the lives of women and girls based on PEPFAR’s mission to help countries achieve epidemic control of HIV/AIDS. The data show that new HIV infections must be reduced in AGYW, or the global community risks losing the extensive progress made towards reaching epidemic control. With support from PEPFAR and private sector partners—the Bill & Melinda Gates Foundation, Gilead Sciences, Girl Effect, Johnson & Johnson and ViiV Healthcare, DREAMS works together with partner governments to deliver a core package of interventions that combines evidence-based approaches that go beyond the health sector, addressing the structural drivers that directly and indirectly increase girls’ HIV risk. Not only is DREAMS an effort to reduce new HIV infections, but it aims to reduce other critical vulnerabilities such as gender-based violence. When girls and young women thrive, the effects are felt throughout their families, communities and countries.