In this approach, an E3 ligase is hijacked by a molecular glue or PROTAC to polyubiquitinate a protein of interest (POI), leading to its degradation. In Cullin RING E3 ligases, the largest group of E3 ligases, the E3 ligase complex works alongside an ubiquitin-loaded E2 enzyme, which transfers ubiquitin to the substrate or POI. This leads to subsequent degradation by the ubiquitinproteasome system (UPS). This catalytic mode of action provides significant advantages, such as extended pharmacological effects, doses reduction, and potentially minimizing adverse effects. While molecular glues identification is often serendipitous, PROTACs can be designed more rationally. However, the boundaries between the two is becoming increasingly blurred. Degraders can overcome cancer resistance mechanisms, such as target amplification or overexpression, through their catalytic activity. Additionally, they can counteract resistance caused by altered ligand binding sites, as even weak binders can still enable efficient degradation. PROTACs for targeted degradation of HDACs were introduced in 2018, and since then, over 100 HDAC PROTACs have been published. Despite the use of many different HDAC ligands, only three E3 ligases have been employed: Cereblon (CRBN), Von Hippel-Lindau (VHL), and the inhibitor of apoptosis protein (IAP), according to PROTAC-DB 3.0. The first PROTAC for targeted degradation of an HDAC was the crebinostat-derived degrader I (Figure ). It used pomalidomide for CRBN recruitment and despite PROTAC I contains a pan-HDAC ligand, only HDAC6 was degraded. PROTAC II and IV are representatives of the first successful recruitment of VHL and IAP, respectively. PROTAC III contains a benzamide for targeting class I HDACs and the switch to a CRBN recruiter shows similar degradation selectivity, but to a lesser extent. The E3 ligase switch from IV to V yielded a different result: Both contain the pan-HDAC inhibitor dacinostat and a polyethylene glycol (PEG) spacer, but the IAP-recruiting IV resulted in HDAC6 degradation, while V degraded HDAC3 and 8 by VHL recruitment. Figure . Comparison of HDAC PROTACs recruiting different E3 ligases. PROTAC I was the first utilization of CRBN for HDAC degradation, while PROTAC II represents the first VHL-based HDAC degrader. PROTAC III shows similar degradation selectivity to PROTAC II, but to a lesser extent by switching back to a CRBN recruiter. The first successful utilization of IAP for targeted HDAC degradation was PROTAC IV and changing the E3 ligase to VHL, represented by PROTAC V , results in a switch of degraded isoforms.