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In addition to common pollutants such as organic matter and nutrients, an ever-growing range of chemicals increasingly threatens the quality of rivers and lakes, as well as the health of aquatic ecosystems. Understanding the main sources and transport pathways of these substances therefore represents a key scientific and management challenge.Within the framework of the Tethys project, a hazardous substance emission model was developed for the Danube River Basin (DRB) through close cooperation among nine Danube countries. The modelling work was based on the systematic collection of concentration and emission data for multiple transport pathways, resulting in a substance-specific inventory that served as the foundation for emission modelling.A common Danube-wide modelling tool was implemented using the MoRE (Modelling of Regional Emissions) framework. The model represents between four and eleven emission pathways for three substance groups: potentially toxic elements (PTEs), including six heavy metals and arsenic; industrial chemicals represented by the two most widespread per- and polyfluoroalkyl substances (PFOS and PFOA); and human pharmaceuticals represented by a widely used analgesic (diclofenac) and a psychoactive compound (carbamazepine). In addition to major point sources, the model accounts for numerous diffuse pathways, including groundwater, surface runoff, tile drainage, erosion, atmospheric deposition, and various legacy pollution sources such as landfills, aerodromes, and industrial disposal sites.The modelling framework includes a newly developed retention approach that explicitly accounts for riverine retention for each substance group, as well as an uncertainty assessment module designed to quantify parameter uncertainty. This module is implemented within an R-based computational engine of the MoRE model.Model validation was performed using long-term river monitoring data from existing operational monitoring networks, complemented by additional datasets collected by partner institutions during project implementation. Discharge data were provided by the participating countries.The modelling results indicate that erosion, groundwater, municipal and industrial wastewater systems are the dominant emission pathways for PTEs, with pronounced spatial variability along the DRB. Point source contributions dominate in the Upper Danube, whereas agricultural-related diffuse pollution becomes increasingly important in the Lower Danube. For PFASs and pharmaceuticals, municipal wastewater represents the main emission pathway in most sub-catchments. In the case of PFASs, soils also act as relevant reservoirs, and associated pathways such as surface runoff, erosion, groundwater flow, and tile drainage may contribute substantially to riverine loads.