The National Institutes of Health (NIH) is issuing a funding opportunity for preclinical proof of concept studies targeting rare diseases through the R21 Exploratory/Developmental Research Grant mechanism. This initiative, designated as RFA-TR-24-023, aims to fund preclinical efficacy studies in established rare disease models. The goal is to demonstrate the viability of therapeutic agents, such as small molecules and biologics, that address significant unmet medical needs. Applications are encouraged from a diverse group of organizations and must include plans for collaboration with a rare disease steering committee. Key dates include an open date for applications starting May 3, 2024, with funding targeted at up to $1.2 million for 3-5 awards in FY 2025. Applications are restricted to non-clinical trial research and must demonstrate the readiness of therapeutic agents through prescribed evidence. The total project period is limited to two years with a maximum budget of $275,000. This funding opportunity recognizes the unique challenges in developing therapeutics for rare diseases, as approximately 30 million Americans are affected by such conditions. The program seeks to bridge funding gaps in drug development to propel promising agents towards clinical trials.