Abstract Cancer remains a leading cause of death in the U.S., posing a significant public health challenge with rising incidence rates among young adults. In response, the Biden administration reignited The Cancer Moonshot initiative in 2022, aiming to reduce cancer mortality by 50% over the next 25 years. However, as there remains different mortality rates across subpopulations defined by race and ethnicity, the 50% translates into much more or less depending on the starting point for each group. Achieving this goal would require a 57.0% decrease for Black Americans, 51.9% decrease for White Americans, 21.4% for Asian Americans, 31.0% decrease for Hispanics, and 41.3% decrease for American Indian/Alaska Natives. This study examines the trends in in U.S. cancer incidence, 5-year survival, and mortality during 1992-2022 with a focus on the five leading cancers (lung, colorectal, breast, pancreas, prostate) stratified by race and ethnicity. From 2008-2020, overall cancer death rates have declined by 1.18%/year with attribution to declining lung cancer rates (-2.75%/year, 2005-2020) and anti-smoking campaigns. Estimates have been made on how to meet the Cancer Moonshot through primary, secondary, and tertiary prevention, but these rates have not factored in the different starting points nor racial disparities that exist. Progress has been heterogenous across racial/ethnic groups. Non-Hispanic Black communities continue to face excessive cancer burden compared to counterparts and have had the slowest declines in annual percent changes for mortality. To reach the Moonshot’s mortality goals in 2047, an annual decline of 1.78% across all racial and ethnic groups is needed. However, the required mortality reductions vary by cancer type and are lower for Non-Hispanic Blacks and Non-Hispanic American Indians/Alaska Natives due to inadequate access to screening and treatment. This study delineates the need for multi-level, culturally tailored interventions to improve cancer prevention, screening, and treatment accessibility. To achieve Moonshot objectives, it is imperative to increase the number of on-site patient navigators, enhance accessibility through health education and transportation services, and promote digital campaigns for primary and secondary prevention services. Despite discrepancies in interventions and policy practices, enhancing the cultural competence and holistic nature of these interventions will strengthen efforts towards health equity. These approaches can better serve high-risk groups and alleviate racial disparities in cancerous outcomes. Citation Format: Sukhmani Kaur, Rebecca Kehm, Mary Beth Terry. Addressing Moonshot limitations: High-risk racial disparities in leading cancers [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A005.