Despite significant recent advancements, global hydrological models and their input databases still show limited capabilities in supporting many spatially detailed research questions and integrated assessments, such as required in freshwater ecology or applied water resources management. In order to address these challenges, the scientific community needs to create improved large-scale datasets and more flexible data structures that enable the integration of information across and within spatial scales; develop new and advanced models that support the assessment of longitudinal and lateral hydrological connectivity; and provide an accessible modeling environment for researchers, decision makers, and practitioners. As a contribution, we here present a new modeling framework that integrates hydrographic baseline data at a global scale (enhanced HydroSHEDS layers and coupled datasets) with new modeling tools, specifically a river network routing model (HydroROUT) that is currently under development. The resulting ‘hydro-spatial fabric’ is designed to provide an avenue for advanced hydro-ecological applications at large scales in a consistent and highly versatile way. Preliminary results from case studies to assess human impacts on water quality and the effects of dams on river fragmentation and downstream flow regulation illustrate the potential of this combined data-and-modeling framework to conduct novel research in the fields of aquatic ecology, biogeochemistry, geo-statistical modeling, or pollution and health risk assessments. The global scale outcomes are at a previously unachieved spatial resolution of 500 m and can thus support local planning and decision making in many of the world's large river basins. Copyright © 2013 John Wiley & Sons, Ltd.