Urban water cycles are threatened in many ways by human activities, including the discharge of chemicals by industrial and household effluents. Since more than a decade it has been recognised that the active ingredients of human pharmaceuticals contribute to the chemical contamination of urban surface waters and may pose a serious risk to the environment. Pharmaceuticals reach the aquatic environment due to their everyday use, excretion by humans and incomplete degradation in sewage treatment works. Their environmental concentrations are generally low. Due to their biologic activity, however, pharmaceuticals are considered as candidate compounds for low-level and chronic effects. Indeed, some pharmaceuticals, such as compounds interfering with reproductive hormones, provoke long-term effects on aquatic vertebrates in the ng/L range. Therefore, appropriate regulations for the environmental risk assessment as part of the approval of new medicines have been established. It was criticised, however, that these guidelines would not have been able to detect or predict the effects of some compounds with already known environmental impact. Thus, approaches for amending existing guidelines have been suggested. In this review, we give a brief overview on current and novel approaches for the prospective environmental risk assessment of human pharmaceuticals in the aquatic environment. In particular, we compare different strategies to identify potential ecotoxic effects and the possible applications within a regulatory framework. We indicate a number of tools that could improve the detection of compounds with potential low-level effects or hitherto unknown but relevant alternative mode of actions with implications for long-term effects.