Despite considerable progress in ecotoxicology, it has become clear that this discipline cannot answer its central questions, such as, “What are the effects of toxicants on biodiversity?” and “How the ecosystem functions and services are affected by the toxicants?”. We argue that if such questions are to be answered, a paradigm shift is needed. The current bottom-up approach of ecotoxicology that implies the use of small-scale experiments to predict effects on the entire ecosystems and landscapes should be merged with a top-down macroecological approach that is directly focused on ecological effects at large spatial scales and consider ecological systems as integral entities. Analysis of the existing methods in ecotoxicology, ecology, and environmental chemistry shows that such integration is currently possible. Therefore, we conclude that to tackle the current pressing challenges, ecotoxicology has to progress using both the bottom-up and top-down approaches, similar to digging a tunnel from both ends at once.