This report represents a synthesis and integration of basic and applied research into a system-scale model of the Hanford 300 Area groundwater uranium plume, supported by the U.S. Department of Energy (DOE) Richland Operations Office (RL). The report integrates research findings and data from DOE Office of Science (SC), Office of Environmental Management (EM), and DOE-RL projects, and from the site remediation and closure contractor, Washington Closure Hanford, LLC. The threedimensional, system-scale model addresses water flow and reactive transport of uranium for the coupled vadose zone, unconfined aquifer, and Columbia River shoreline of the Hanford 300 Area. The system-scale model of the 300 Area was developed to be a decision-support tool to evaluate processes of the total system affecting the groundwater uranium plume. The model can also be used to address "what if" questions regarding different remediation endpoints, and to assist in design and evaluation of field remediation efforts. For example, the proposed cleanup plan for the Hanford 300 Area includes removal, treatment, and disposal of contaminated sediments from known waste sites, enhanced attenuation of uranium hot spots in the vadose and periodically rewetted zone, and continued monitoring of groundwater with institutional controls. Illustrative simulations of polyphosphate infiltration were performed to demonstrate the ability of the system-scale model to address these types of questions. The use of this model in conjunction with continued field monitoring is expected to provide a rigorous basis for developing operational strategies for field remediation and for defining defensible remediation endpoints. The system-scale flow and reactive transport model of the 300 Area subsurface was implemented using the simulator eSTOMP ("e" for extreme scale), developed recently by Pacific Northwest National Laboratory (PNNL) under the laboratory-directed research and development program's Extreme-Scale Computing Initiative. This is a parallel version of the STOMP (Subsurface Transport Over Multiple Phases) simulator that was developed specifically to allow for simulation with faster run times and/or for larger-scale subsurface flow and reactive transport problems. All model simulations with eSTOMP were performed on Olympus, a high-performance computing cluster supported by PNNL's institutional computing program. Data from laboratory and field experiments performed for the Integrated Field Research Challenge (IFRC) project, supported by DOE-SC, and from other DOE-EM and DOE-RL projects, were used for model development and testing. A column experiment performed on an intact, uranium-contaminated core sample collected from the IFRC site was used as a small-scale validation test for a uranium surface complexation reaction network implemented with eSTOMP. Experimental data from this and other laboratory column experiments with 300 Area sediments were used to develop an alternative reaction network that also accounts for reactions associated with polyphosphate amen...