Updated publication reference for PubMed record(s): 31959954. We introduce tissue Thermal Proteome Profiling (tissue-TPP) which enables the discovery of drug targets and off-targets as well as measurements of target occupancy in tissue samples derived from dosed animals. Here we report the first proteome-wide thermal stability map of tissues and organ-specific target profiles of the non-covalent histone deacetylase inhibitor, panobinostat. In addition, we devised blood-CETSA/TPP to monitor target and off-target engagement directly in whole blood.