Although the use of tissue concentrations (residues) of chemical contaminants as the dose metric to characterize chemical toxicity to aquatic organisms has been gaining acceptance over the past 20 years, tissue concentrations are less commonly used in water quality management and have yet to be formally adopted as benchmarks or environmental quality standards (EQS). This synthesis paper addresses advantages and disadvantages for the development and application of tissue-based EQS as an alternative and supplement to exposure-based EQS determined with water and sediment concentration data. Tissue-based EQS can be readily developed in parallel with conventional toxicity tests, and achieved by quantification of chemical concentrations in tissue alongside traditional concentration-response toxicity testing. Tissue-residue toxicity metrics can be used as benchmarks for screening and monitoring water and sediment quality, to derive equivalent water or sediment EQS, and for ecological risk assessments and weight of evidence approaches for assessing ecosystem impairment. Tissue-based toxicity metrics and associated EQS provide several advantages; however, there are some limitations to consider and key knowledge gaps to fill.