Targeted protein degradation (TPD) is a promising therapeutic mechanism to engage challenging and previously intractable protein targets. Modalities such as proteolysis targeting chimeras (PROTAC) and molecular glues have attracted significant interest. PROTACs are heterobifunctional small molecules that recruit proteins of interest to a ubiquitin E3 ligase. The proximity leads to ubiquitination of the target protein and subsequent degradation. Alternatively, molecular glues bind to neosubstrates presented when two or more proteins form a complex, including E3 ligases, that can initiate protein degradation. Hit identification strategies often rely on label-based binding assays that are cumbersome, tedious, and unreliable. Affinity selection MS addresses some limitations, yet is often still slow and restrictive, compromising data quality and delaying progress. SAMDI-ASMS uniquely combines surface chemistry and mass spectrometry, offering key benefits for identifying non-covalent binders to virtually any target, and offers significant advantages for hit finding efforts for TPD strategies.