Pesticides applied on land are commonly transported by runoff or spray drift to aquatic ecosystems, where they are potentially toxic to fishes and other nontarget organisms. Pesticides add to and interact with other stressors of ecosystem processes, including surface-water diversions, losses of spawning and rearing habitats, nonnative species, and harmful algal blooms. Assessing the cumulative effects of pesticides on species or ecological functions has been difficult for historical, legal, conceptual, and practical reasons. To explore these challenges, we examine current-use (modern) pesticides and their potential connections to the abundances of fishes in the San Francisco Estuary (California). Declines in delta smelt (Hypomesus transpacificus), Chinook salmon (Oncorhynchus tshawytscha), and other species have triggered mandatory and expensive management actions in the urbanizing estuary and agriculturally productive Central Valley. Our inferences are transferable to other situations in which toxics may drive changes in ecological status and trends.