Abstract Since 2014, NCI has been building data science platforms to integrate genetic information about tumors with data on how patients respond to therapy. This work advances the 2011 Institute of Medicine recommendation to build a unified system to collect, integrate, and share cancer data from the widest possible set of research studies. NCI is working to fulfill this recommendation by establishing an NCI Cancer Research Data Commons (CRDC), virtual, expandable informatics infrastructure and data repositories, which are designed to support the work of the NCI intramural and extramural cancer research communities. The CRDC is a crucial component of a broader National Cancer Data Ecosystem that spans discovery research, patient participation, and population surveillance. The development of such an ecosystem was a key recommendation of the Cancer Moonshot Blue Ribbon Panel. NCI has been developing the Cancer Research Data Commons based on the understanding that big data emerging from research programs, precision medicine trials, and surveillance can be used to develop and inform models that predict how patients will response to treatment. Numerous NCI-funded programs will provide key data for this ecosystem, including a variety of discovery programs, clinical trials, cohort studies, and NCI’s Surveillance, Epidemiology, and End Results program (SEER), which is the most comprehensive source of population-based information in the country that includes stage of cancer, detailed characterization of the cancer including important biomarkers at the time of diagnosis, and performs active follow-up to determine patient survival data. The CRDC is designed to be as flexible as possible so that many types and sources of data can be accessed in a unified, interoperable manner. It is this data interoperability that facilitates novel insights into cancer biology and treatment. During the past several years, NCI has been developing key building blocks that comprise the CRDC. These building blocks include (i) Data Commons Nodes, which are repositories that house harmonized data from multiple programs; (ii) Cloud Resources, which provide workspaces, analysis capabilities, and access to elastic computing resources in commercial cloud environments; (iii) a Data Commons Framework (DCF), which is a set of modular, reusable services that maximize interoperability across cancer datatypes and repositories, increase sustainability, and reduce future resource cost; and (iv) semantics services to support data models, vocabularies, ontologies, data submission, and cross-domain queries. The modular design of the CRDC means that new services and components can be added flexibly, which allows for new data sources and new technologies to become integrated as they become available. The NCI Cancer Research Data Commons will serve as a platform for understanding fundamental cancer biology questions, including cancer initiation, progression, and recurrence, in ways that support new prevention, treatment, and surveillance strategies. Citation Format: Anthony Kerlavage. A modern data commons approach to advance population science [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr IA24.