Micro- and nanoplastics (MNPs) are increasingly detected in environmental and biological systems, raising concerns about their potential long-term impacts on human health and ecosystems. Despite growing awareness, significant knowledge gaps and uncertainties remain regarding their persistence, bioaccumulation, and detrimental interactions within biological systems. However, as our experience with other classes of synthetic substances, such as CFCs and their ozone-depleting effects, has shown, originally harmless substances can exhibit dangerous properties with dramatic consequences in certain environments. To avoid such unpleasant surprises, prospective risk assessment approaches are necessary to enable a risk-minimizing and sustainable design of new materials and thereby support the Safe and Sustainable by Design Strategy (SSbD) and Circular Economy Action Plan of the EU (2020; 2022). One of the aims of the PlasticsFatE (Plastics Fate and Effects in the Human Body) Project, supported by Horizon 2020, was to develop a risk assessment and management strategy for plastics based on a Decision Support System (DSS). Developing this tool has shown which knowledge gaps still exist and limit the use of current risk assessment approaches for plastics. This policy brief summarizes the difficulties we still face in the development and application of risk assessment tools and formulates research tasks to enable robust and sustainable risk assessment and risk management for plastics in the future.