INTRODUCTION: The "DREAMS Partnership" promotes a multi-sectoral approach to reduce adolescent girls and young women's (AGYW) vulnerability to HIV in sub-Saharan Africa. Despite widespread calls to combine structural, behavioural and biomedical HIV prevention interventions, this has not been delivered at scale. In this commentary, we reflect on the two-year rollout of DREAMS in a high HIV incidence, rural and poor community in northern KwaZulu-Natal, South Africa to critically appraise the capacity for a centrally co-ordinated and AGYW-focused approach to combination HIV prevention to support sustainable development for adolescents. DISCUSSION: DREAMS employed a directed target-focused approach in which local implementing partners were resourced to deliver defined packages to AGYW in selected geographical areas over two years. We argue that this approach, with high-level oversight by government and funders, enabled the rapid roll-out of ambitious multi-sectoral HIV prevention for AGYW. It was most successful at delivering multiple interventions for AGYW when it built on existing infrastructure and competencies, and/or allocated resources to address existing youth development concerns of the community. The approach would have been strengthened if it had included a mechanism to solicit and then respond to the concerns of young women, for example gender-related norms and how young women experience their sexuality, and if this listening was supported by versatility to adapt to the social context. In a context of high HIV vulnerability across all adolescents and youth, an over-emphasis on targeting specific groups, whether geographically or by risk profile, may have hampered acceptability and reach of the intervention. Absence of meaningful engagement of AGYW in the development, delivery and leadership of the intervention was a lost opportunity to achieve sustainable development goals among young people and shift gender-norms. CONCLUSIONS: Centrally directed and target-focused scale-up of defined packages of HIV prevention across sectors was largely successful in reaching AGYW in this rural South African setting rapidly. However, to achieve sustainable and successful long-term youth development and transformation of gender-norms there is a need for greater adaptability, economic empowerment and meaningful engagement of AGYW in the development and delivery of interventions. Achieving this will require sustained commitment from government and funders.