The usual procedures for ecological risk assessment (ERA) have been based for decades on simplified approaches in order to provide basic information on the huge amount of chemicals introduced into the environment. These approaches allowed the development of international regulatory tools capable of substantially reducing the adverse effects on ecosystems in developed countries. Nevertheless, these approaches suffer from a lack of ecological realism and are poorly suitable for understanding the actual consequences for ecosystem health. The need for more ecologically-based approaches is now recognized by the scientific community and has been highlighted by a recent document of the European Commission. In this paper, a synthesis is presented of the most important issues and the need for research to improve the ecological realism of exposure and effect assessment and the tools that should be developed to reach this objective. In particular, the major challenges are the following: the effects of variable exposure patterns; the vulnerability of ecosystems; the indirect ecological effects; the responses to multiple stress factors; the improvement of ecological modeling. The possibilities for using new scientific achievements in regulatory ERA are also discussed.