Legacy and current-use contaminants enter into and accumulate throughout the San Francisco Bay−Delta (Bay−Delta), and are present at concentrations with known effects on species important to this diverse watershed. There remains major uncertainty and a lack of focused research able to address and provide understanding of effects across multiple biological scales, despite previous and ongoing emphasis on the need for it. These needs are challenging specifically because of the established regulatory programs that often monitor on a chemical-by-chemical basis, or in which decisions are grounded in lethality-based endpoints. To best address issues of contaminants in the Bay−Delta, monitoring efforts should consider effects of environmentally relevant mixtures and sub-lethal impacts that can affect ecosystem health. These efforts need to consider the complex environment in the Bay−Delta including variable abiotic (e.g., temperature, salinity) and biotic (e.g., pathogens) factors. This calls for controlled and focused research, and the development of a multi-disciplinary contaminant monitoring and assessment program that provides information across biological scales. Information gained in this manner will contribute toward evaluating parameters that could alleviate ecologically detrimental outcomes. This review is a result of a Special Symposium convened at the University of California−Davis (UCD) on January 31, 2017 to address critical information needed on how contaminants affect the Bay−Delta. The UCD Symposium focused on new tools and approaches for assessing multiple stressor effects to freshwater and estuarine systems. Our approach is similar to the recently proposed framework laid out by the U.S. Environmental Protection Agency (USEPA) that uses weight of evidence to scale toxicological responses to chemical contaminants in a laboratory, and to guide the conservation of priority species and habitats. As such, we also aimed to recommend multiple endpoints that could be used to promote a multi-disciplinary understanding of contaminant risks in Bay−Delta while supporting management needs.