A decision tree has been developed for evaluating risks posed by combined exposures to multiple chemicals. The decision tree divides combined exposures of humans and ecological receptors into groups where one or more components are a concern by themselves, where risks from the combined exposures are of low concern, and where there is a concern for the effects from the combined exposures but not from individual chemicals. This paper applies the decision tree to real-world examples of exposures to multiple chemicals, evaluates the usefulness of the approach, and identifies issues arising from the application. The decision tree was used to evaluate human health and ecological effects from the combined exposure to 559 mixtures of substances measured in surface waters and effluents. The samples contained detectable levels of 2 to 49 substances. The key findings were, 1) the need for assessments of the combined exposures varied for ecological and human health effects and with the source of the monitoring data, 2) the majority of the toxicity came from one chemical in 44% of the exposures (human health) and 60% of exposures (ecological effects), 3) most cases, where risk from combined exposures was a concern, would have been identified using chemical-by-chemical assessments. Finally, the tree identified chemicals where data on the mode of action would be most useful in refining an assessment. The decision tree provided useful information on the need for combined risk assessments and guidance on the questions that should be addressed in future research.