Many contaminants in the California Bay–Delta (Bay–Delta) exceed regulatory standards, affect aquatic species, and potentially affect human health. Recent studies provide multiple lines of evidence that contaminants affect species of concern in the Bay–Delta (e.g., the decline of several important fish species referred to as the “Pelagic Organism Decline” or POD). Contaminants occur as dynamic complex mixtures and exert effects at multiple levels of biological organization. Multiple chemicals impair processes at cellular and physiological levels (measured as growth, development, and behavior abnormalities), and when viability and reproductive output are affected, populations are affected. As an important example, the population decline of the endangered Delta Smelt (Hypomesus transpacificus) is significantly associated with multiple stressors, including insecticide use. New analyses presented in this paper show significant correlations between pyrethroid use and declining abundance of POD fish species. Water sampled from the Bay–Delta causes multiple deleterious effects in fish, and Delta Smelt collected from the Bay–Delta exhibit contaminant effects. Fish prey items are also affected by contaminants; this may have an indirect effect on their populations. Co-occurrence with thermal changes or disease can exacerbate contaminant effects. Contaminants also pose threats to human health via consumption of fish and shellfish, drinking water, and contact recreation, in particular, mercury, cyanobacteria toxins, disinfection byproducts, pathogens, pesticides, and pharmaceuticals and personal care products. The role of contaminants in the decline of Bay–Delta species is difficult to accurately assess in a complex, dynamic system. However, tools and approaches are available to evaluate contaminant effects on Bay–Delta species, and separate the effects of multiple stressors. Integrated monitoring and focused mechanistic studies are instrumental for addressing management needs. Effect and risk assessments should be conducted for different species across multiple life stages, with emphasis on early life stages of highpriority Bay–Delta species.