The UPS process involves an enzyme cascade that results in ubiquitination of the protein of interest (POI). Ubiquitination is at the heart of both proteasomal and autophagy-mediated protein degradation, with E3 ligases as the critical components of the ubiquitination cascade. Out of the more than 600 E3 ubiquitin ligases encoded by the human genome, there are only a few that have been exploited for targeted protein degradation, for example, cereblon (CRBN), VHL, MDM2, DDB1, DCAF15, and SCF βTRCP. These subunits can be targeted by degraders that cause conformational change which promote the formation of a ternary complex with the POI. In principle, the formation of a ternary complex induces molecular proximity between the catalytic site of the E3 ligase and the POI, prompting ubiquitin transfer and subsequent proteasomal degradation of the POI. Identifying successful strategies for discovering ligands that bind to E3 ligases becomes an attractive and exciting research objective. Compared to the traditional pharmacological target protein inhibition, protein degradation offers two crucial advantages. First, targeted degradation is a catalytic process because degraders act via transient binding rather than competitive occupancy and successfully dissociate after promoting polyubiquitination of the disease-causing protein. As such, a single degrader can destroy many copies of a pathogenic protein thereby providing a greater efficiency at very low doses. Second, while protein inhibitors block the active site of a pathogenic protein, degraders ablate all of its functions, providing higher sensitivity to drug-resistant targets and a better chance to affect nonenzymatic protein functions. 13-15 Many key discoveries have contributed to advancing the targeted protein degradation notion as we know it today. The earliest-known published description of the concept of chimeric degraders is in a patent filed in 1999 by a biotech company, Proteinix, proposing taking over the cellular protein-degradation system (Figure ). The concept of utilizing the ubiquitin-driven natural protein degradation system for therapeutic purposes was focused on designing small molecules that recruit E3 ligases for degradation of a POI (Table ). In 2001, the first in vitro proof-of-concept study was published, demonstrating that a peptide-based protein-targeting chimeric molecule, Protac-1, recruiting E3 ligase β-TRCP, successfully led to the degradation of a cancer-associated protein, MetAP2; thus, the name PROTAC (PROteolysis-Targeting Chimera) was introduced. Later on, the finding of a peptide from HIF1α, which binds the VHL E3 ligase, resulted in the construction of cell penetrating PROTACs, which degraded a variety of proteins (Table ). As indicated, these early PROTACs contained peptide ligands for the E3 ligase; the report of a canonical small molecule PROTAC -an androgen receptor (AR) degrader using nutlin-3 for recruiting of MDM2 -was published in 2008. This, and the later discovery of small-molecule mimetics of the HIF1α peptide , expedited the rational design of small molecular PROTACs. Figure . Timeline of major targeted protein degraders research and development milestones