Abstract In the era of big data and artificial intelligence, biomedical research and healthcare have been presented with unprecedented opportunities for improving the understanding of cancer biology. In addition, the Open Science Initiative aims to shift the current paradigm of research practice towards broad sharing and public access to research findings as the norm. Big data in oncology usually includes a combination of genomic sequencing, proteomics, medical imaging, electronic health records, payor records, and other data sources from pharmaceutical research, wearables, and medical devices. While combining, linking, and analyzing data from different sources across research and healthcare enterprises is key to realizing the promise of big data and a health learning system, it poses tremendous challenges for researchers and implementers to understand the nuances of relevant policies, laws, and regulations while striving for broad, equitable, timely and responsible data sharing, as well as tackling issues in data quality, harmonization, interoperability, and security. Herein, we aim to shine a light on the ever-evolving landscape of data privacy regulations, laws, and policies that govern different touch points of a patient's journey where data are collected for research and healthcare purposes throughout the lifecycle that would impact data-sharing outcomes. We hope the illumination of a complex landscape of data governance framework to consider for many data sources will facilitate broad community engagement including data scientists and technologists, patients and advocacy groups, and policymakers to maximize open data and science while protecting patient privacy and confidentiality. Citation Format: Ying Huang, Heather Basehore, Emily S. Boja, Jaime M. Guidry Auvil. Harness the power of data to improve cancer care - Understanding the complex landscape of health policies and regulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1303.