Environmental risk assessment is typically uncertain due to different perceptions of the risk problem and limited knowledge about the physical, chemical, and biological processes underlying the risk. The present paper provides a systematic overview of the implications of different types of uncertainty for risk management, with a focus on risk-based management of river basins. Three different types of uncertainty are distinguished: 1) problem definition uncertainty, 2) true uncertainty, and 3) variability. Methods to quantify and describe these types of uncertainty are discussed and illustrated in 4 case studies. The case studies demonstrate that explicit regulation of uncertainty can improve risk management (e.g., by identification of the most effective risk reduction measures, optimization of the use of resources, and improvement of the decision-making process). It is concluded that the involvement of nongovernmental actors as prescribed by the European Union Water Framework Directive (WFD) provides challenging opportunities to address problem definition uncertainty and those forms of true uncertainty that are difficult to quantify. However, the WFD guidelines for derivation and application of environmental quality standards could be improved by the introduction of a probabilistic approach to deal with true uncertainty and a better scientific basis for regulation of variability.