Tissue residue-based toxicity benchmarks (TRBs) have typically been developed using the results of individual studies selected from the literature. In the past, TRBs have been developed using a point estimate (e.g., LC50 value) reported in a study on a single species deemed to be most closely related to the receptor of interest. Despite attempts to maximize the protectiveness and relevance of TRBs, their relationship to specific receptors remains uncertain, and their general applicability for use in broader ecological risk assessment contexts is limited. This article proposes a novel framework that establishes benchmarks as distributions rather than single-point estimates. Benchmark distributions allow the user to select a tissue concentration that is associated with the protection of a specific percentage of organisms, rather than linked to a specific receptor. A methodology is proposed for searching, reviewing, and analyzing linked, tissue residue effect data to derive benchmark distributions. The approach is demonstrated for contaminants having a dioxin-like mechanism of toxic action and is based on residue effects data for 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and equivalents in early life stage fish. The calculated tissue residue benchmarks for 2,3,7,8-TCDD toxic equivalency (TEQ) derived from the resulting distribution could range from 0.057- to 0.699-ng TCDD/g lipid depending on the level of protection needed; the lower estimate is protective of 99% of fish species whereas the higher end is protective of 90% of fish species.