The National Institutes of Health (NIH), under the Department of Health and Human Services, has issued a Notice of Funding Opportunity (NOFO) titled "Innovation for HIV Vaccine Discovery” (PAR-23-169) to support high-risk, high-impact research aimed at early discovery of innovative vaccine strategies against HIV. This NOFO reissues previous funding directives and is focused on revolutionary approaches that may prevent HIV infection, encouraging participation from new and diverse principal investigators, including early-stage and at-risk researchers. Applications are open until August 2, 2025, with a principal funding budget of $350,000 per year, with potential extra funds for projects involving nonhuman primate studies. Unique to this opportunity, a Go/No-Go decision framework is required, where funding for later years will be contingent upon the achievement of specific, measurable goals within the first two years. The NIH is looking for projects that challenge current paradigms and foster interdisciplinary collaborations, with an emphasis on novel vaccine strategies that engage the immune system's breadth and durability against HIV. This initiative aligns with the ongoing priority of developing an effective HIV vaccine, addressing significant public health concerns and leveraging advancements in immunological research and technology.