Agricultural and urban development alters nitrogen and other biogeochemical cycles in rivers worldwide. Because such biogeochemical processes cannot be measured empirically across whole river networks, simulation models are critical tools for understanding river-network biogeochemistry. However, limitations inherent in current models restrict our ability to simulate biogeochemical dynamics among diverse river networks. We illustrate these limitations using a river-network model to scale up in situ measures of nitrogen cycling in eight catchments spanning various geophysical and land-use conditions. Our model results provide evidence that catchment characteristics typically excluded from models may control river-network biogeochemistry. Based on our findings, we identify important components of a revised strategy for simulating biogeochemical dynamics in river networks, including approaches to modeling terrestrial–aquatic linkages, hydrologic exchanges between the channel, floodplain/riparian complex, and subsurface waters, and interactions between coupled biogeochemical cycles.