We discuss the importance of selected natural abiotic and biotic factors in ecological risk assessment based on simplistic laboratory bioassays. Although it is impossible to include all possible natural factors in standard lower-tier ecotoxicological testing, neglecting them is not an option. Therefore, we try to identify the most important factors and advocate redesigning standard testing procedures to include theoretically most potent interactions. We also point out a few potentially important factors that have not been studied enough so far. The available data allowed us to identify temperature and O2 depletion as the most critical factors that should be included in ecotoxicity testing as soon as possible. Temporal limitations and fluctuations in food availability also appear important, but at this point more fundamental research in this area is necessary before making decisions on their inclusion in risk assessment procedures. We propose using specific experimental designs, such as Box-Behnken or Central Composite, which allow for simultaneous testing of 3 or more factors for their individual and interactive effects with greater precision and without increasing the effort and costs of tests dramatically. Factorial design can lead to more powerful tests and help to extend the validity of conclusions. Finally, ecological risk assessment procedures should include information on animal behavior, especially feeding patterns. This requires more basic studies, but already at this point adequate mechanistic effect models can be developed for some species.