Human exposure occurs simultaneously to multiple environmental and/or occupational chemicals. As this presentation will demonstrate, chemicals may interact in multiple ways, including via toxicokinetic modifications or through their common impact on the same target systems, organs or molecules. Importantly, such interactions do not require interacting chemicals to be structurally or mechanistically similar. Yet both our understanding of health effects, and the derivation of safe exposure levels remain premised on outcomes of chemicals studied in isolation. Current efforts to address mixtures have focused largely on chemicals that share structural or mechanistic similarity, but these comprise only a small fraction of the total problem. Studies of mixtures of chemicals that are co-occurring and that share biological targets and common adverse physiological consequences may provide a strategy to address this far broader problem. Such an approach defines those chemicals agents that should be studied as mixtures in a context directly related to public health.