Waters in the Great Lakes basin contain more than 400 contaminant chemicals that potentially affect fishery resources, commerce, and human inhabitants. We determined in the laboratory the effects of selected contaminants on the toxicity of the widely used lampricides TFM (3-trifluoromethyl-4-nitrophenol) and Bayer 73 (2′,5-dichloro-4′-nitrosalicylanilide) to three species of fish—rainbow trout (Salmo gairdneri), white sucker (Catostomus commersoni), and fathead minnow (Pimephales promelas). The fish were exposed to paired mixtures of lampricides and selected contaminants in standardized, acute static toxicity tests to determine the resulting type of response—less than additive, additive, or greater than additive (synergistic). As expected, the toxicities of combinations of lampricides with organic pesticides, metal, industrial or municipal pollutants, and tannic acid were mostly additive. However, the toxicity of a combination of TFM, Delnav, and malathion was synergistic, and extremely small quantities of each chemical became lethal when mixed. The concentration that produced 50% mortality was 1.64 mg/L for TFM alone but only 0.041 mg/L for TFM with the pesticides. Toxicities of the pesticides in the combination also increased commensurately. The triple combination of chemicals produced extraordinary synergism and effectively demonstrated the hazards that may result if certain chemical combinations occur in the aquatic environment. However, synergism is not the only kind of toxic action that produces hazards to aquatic organisms. All three types of toxic action are of concern because toxic units produced by contaminant chemicals add to the toxic units of applied management chemicals. Since the toxicity of the majority of chemical combinations is simply additive, this cumulative toxic action contributes more total units to aquatic environments than the extreme actions of less than additive and synergism. The toxicity of the lampricide TFM, as well as other management chemicals, is reinforced by the presence of any contaminant that contributes additional units of toxicity. Therefore, all types of cumulative toxic action should be of concern to people and agencies involved with protecting the environment.