The Department of Health and Human Services, through the National Center for Complementary and Integrative Health (NCCIH), has issued a funding opportunity for the NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33). This initiative encourages applications for early-phase clinical trials involving natural products such as botanicals and dietary supplements, emphasizing a strong scientific basis for further testing. The award consists of two phases: the R61 phase, which provides up to three years of funding for milestone-driven pharmacokinetics and target engagement studies, and the R33 phase, which may add another three years contingent on achieving the R61 milestones. Trials must focus on demonstrating measurable effects on target mechanisms rather than solely clinical symptom changes. Key aspects include guidelines for demonstrating target engagement, necessary preliminary data, and a plan for enhancing diverse perspectives. Applications are expected to include hypotheses, statistical methods, safety measurements, and a strong recruitment strategy. The project's ultimate aim is to inform decisions about further development or full-scale efficacy trials of the proposed natural products, aligning with NCCIH's goals of rigorous research in complementary and integrative health approaches.