A modeling approach that was used to predict the toxicity of dissolved single and multiple metals to trout is extended to stream benthic macroinvertebrates, freshwater zooplankton, and Daphnia magna. The approach predicts the accumulation of toxicants (H, Al, Cd, Cu, Ni, Pb, and Zn) in organisms using 3 equilibrium accumulation models that define interactions between dissolved cations and biological receptors (biotic ligands). These models differ in the structure of the receptors and include a 2-site biotic ligand model, a bidentate biotic ligand or 2-pKa model, and a humic acid model. The predicted accumulation of toxicants is weighted using toxicant-specific coefficients and incorporated into a toxicity function called Tox, which is then related to observed mortality or invertebrate community richness using a logistic equation. All accumulation models provide reasonable fits to metal concentrations in tissue samples of stream invertebrates. Despite the good fits, distinct differences in the magnitude of toxicant accumulation and biotic ligand speciation exist among the models for a given solution composition. However, predicted biological responses are similar among the models because there are interdependencies among model parameters in the accumulation–Tox models. To illustrate potential applications of the approaches, the 3 accumulation–Tox models for natural stream invertebrates are used in Monte Carlo simulations to predict the probability of adverse impacts in catchments of differing geology in central Colorado (USA); to link geology, water chemistry, and biological response; and to demonstrate how this approach can be used to screen for potential risks associated with resource development.