Quantitative prediction of natural and induced phenomena in fractured rock is one of the great challenges in the Earth and Energy Sciences with far-reaching economic and environmental impacts. Fractures occupy a very small volume of a subsurface formation but often dominate flow, transport and mechanical deformation behavior. They play a central role in CO₂ sequestration, nuclear waste disposal, hydrogen storage, geothermal energy production, nuclear nonproliferation, and hydrocarbon extraction. These applications require prediction of fracture-dependent quantities of interest such as CO₂ leakage rate, hydrocarbon production, radionuclide plume migration, and seismicity; to be useful, these predictions must account for uncertainty inherent in subsurface systems. Here, we review recent advances in fractured rock research that cover field- and laboratory-scale experimentation, numerical simulations, and uncertainty quantification. We discuss how these have greatly improved the fundamental understanding of fractures and one’s ability to predict flow and transport in fractured systems. Dedicated field sites provide quantitative measures of fracture flow that can be used to identify dominant coupled processes and to validate models. Laboratory-scale experiments fill critical knowledge gaps by providing direct observations and measurements of fracture geometry and flow under controlled conditions that cannot be obtained in the field. Physics-based simulation of flow and transport provide a bridge in understanding between controlled simple laboratory experiments and the massively complex field-scale fracture systems. Finally, we review the use of machine learning-based emulators to rapidly investigate different fracture property scenarios and to accelerate physics-based models by orders of magnitude to enable uncertainty quantification and near real-time analysis.