Proteomics has the potential to elucidate complex patterns of toxic action attributed to its unique holistic a posteriori approach. In the case of toxic compounds for which the mechanism of action is not completely understood, a proteomic approach may provide valuable mechanistic insight. This review provides an overview of currently available proteomic techniques, including examples of their application in toxicological in vivo and in vitro studies. Future perspectives for a wider application of state-of-the-art proteomic techniques in the field of toxicology are discussed. The examples concern experiments with dioxins, polychlorinated biphenyls, and polybrominated diphenyl ethers as model compounds, as they exhibit a plethora of sublethal effects, of which some mechanisms were revealed via successful proteomic studies. Generally, this review shows the added value of including proteomics in a modern tool box for toxicological studies.