Toward a comprehensive characterization of toxicant responses, systems toxicology requires the integration of different data modalities. Proteomics approaches measure changes in the levels of proteins and their posttranslational modifications, which can closely reflect the biological effects of a toxicant. With a focus on mass spectrometry-based proteomics, we describe the isobaric tag-based approach for quantitative proteomics (iTRAQ® and TMT™) and describe computational approaches to derive biological/mechanistic insights. Specifically, we describe the generation and quantification of mass-spectrometry data and the identification of affected proteins, functional modules, and protein subnetworks. We illustrate these approaches using results from a 90-day rat inhalation toxicology study. Overall, we provide the foundation to employ quantitative proteomics within systems toxicology assessment strategies.