The majority of contaminants exert toxicities by attacking proteins. However, identification of protein targets is extemely challenging due to the huge number of proteins (~20,000 in humans) and dynamic range (>105 copies). We aim to develop different chemistry toolboxes (i.e., thermal stability, photoreactive probes) integrated with quantitative proteomics to identify protein targets of bioactive chemicals. The toolboxes are currently applied to a broad class of chemicals including atmospheric pollutants, disinfection by-products, organophosphate flame retardants, per- and polyfluoroalkyl substances and natural products.