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Assessing global water quality issues requires a multi-pollutant modelling approach. We discuss scientific challenges and future directions for such modeling. Multi-pollutant river models need to integrate information on sources of pollutants such as plastic debris, nutrients, chemicals, pathogens, their effects and possible solutions. In this paper, we first explain what we consider multi-pollutant modelling. Second, we discuss scientific challenges in multi-pollutant modelling relating to consistent model inputs, modelling approaches and model evaluation. Next, we illustrate the potential of global multi-pollutant modelling for hotspot analyses. We show hotspots of river pollution with microplastics, nutrients, triclosan and Cryptosporidium in many sub-basins of Europe, North America and South Asia. Finally, we reflect on future directions for multi-pollutant modelling, and for linking model results to policy-making.