Conceptual and quantitative models were developed to assess time-dependent processes in four sequential experimental stream studies that determined abundances of natural communities of mayfly and caddisfly larvae dosed with single metals (Cd, Co, Cu, Ni, Zn) or multiple metals (Cd+Zn, Co+Cu, Cu+Ni, Cu+Zn, Ni+Zn, Cd+Cu+Zn, Co+Cu+Ni, Cu+Ni+Zn). Metal mixtures contained environmentally relevant metal ratios found in mine drainage. Free metal ion concentrations, accumulation of metals by periphyton, and metal uptake by four families of aquatic insect larvae were either measured (Brachycentridae) or predicted (Ephemerellidae, Heptageniidae, Hydropsychidae) using equilibrium and biodynamic models. Toxicity functions, which included metal accumulations by larvae and metal potencies, were linked to abundances of the insect families. Model results indicated that mayflies accumulated more metal than caddisflies and the relative importance of metal uptake by larvae via dissolved or dietary pathways highly depended on metal uptake rate constants for each insect family and concentrations of metals in food and water. For solution compositions in the experimental streams, accumulations of Cd, Cu, and Zn in larvae occurred primarily through dietary uptake, whereas uptake of dissolved metal was more important for Co and Ni accumulations. Cd, Cu, and Ni were major contributors to toxicity in metal mixtures and for metal ratios examined. Our conceptual approach and quantitative results should aid in designing laboratory experiments and field studies that evaluate metal uptake pathways and metal mixture toxicity to aquatic biota.