The Cellular Thermal Shift Assay (CETSA®) is a well-established label-free technology that assesses protein-ligand interactions in the native cellular environment. Confirmation of Target Engagement (TE) in the relevant physiological environment supports decision making and prioritisations in drug discovery projects. CETSA® Navigate HT is a high-throughput format for screening and/or profiling larger sets of drug molecules and has successfully been applied in e.g., tool finding, hit identification, and hit confirmation efforts. CETSA® Explore is an unbiased mass spectrometry-based, proteome-wide target engagement assessment method which can guide drug discovery projects through target identification, selectivity assessments, and provide insights into biological processes in physiologically relevant conditions. In this presentation, applications of CETSA® in primary screening, hit confirmation, target validation, and selectivity assessment will be presented.