In recent years, targeted protein degradation (TPD) has gained increasing interest due to its potential to overcome limitations of conventional protein inhibition. TPD encompasses two main modalities: molecular glues and proteolysis targeting chimeras (PROTACs). However, the distinction between these approaches is increasingly blurred. Monovalent molecular glues are often identified serendipitously, whereas the discovery and design of the hetero-bivalent PROTACs tend to follow a more rational approach. The latter consist of a protein of interest (POI) ligand and an E3 ligase recruiter, connected by a suitable spacer. This structure enables PROTACs to induce proximity between the POI and an E3 ligase, which is accompanied by an ubiquitinloaded E2 ligase (Figure , center). For Cullin RING ligases (CRLs), representing the major class of E3 ligase complexes, the E2 ligase transfers ubiquitin to the bound substrate/POI, typically leading to polyubiquitination and subsequent degradation via the ubiquitin-proteasome system (UPS). This complex (middle) facilitates polyubiquitination and proteasomal degradation of the POI (bottom left). By binding the E3 ligase covalently, PROTAC and E3 form a pseudo-binary complex capable of recruiting the next POI (cycle on the right).