PPIs depend on the respective E3 and recruited POI and can enhance selectivity of promiscuous POI ligands when incorporated into a PROTAC. Recently, this approach has been applied to the targeted degradation of histone deacetylases (HDACs). HDACs are key components of the epigenetic machinery, with their primary function to hydrolyze acetylated lysine residues on histones. This restores the positive charge on the amine, leading to a more compact chromatin structure. In addition to histones, there are multiple other HDAC substrates, depending on the isoform and some HDACs are part of multiprotein complexes. The enzyme family is divided into four zinc-dependent classes consisting of eleven isoforms: class I (HDAC1-3 and 8), class IIa (HDAC4, 5, 7 and 9), class IIb (HDAC6 and 10), and class IV (HDAC11). HDACs are compelling targets in oncology, as their overexpression is associated with poor prognosis in diseases such as multiple myeloma, adenocarcinoma of the lung, and acute myeloid leukemia. Furthermore, HDAC inhibition disrupts the cell cycle, reduces DNA-damage response, and impairs metastasis, angiogenesis, and proliferation. Additionally, HDAC inhibition can enhance apoptosis and cell differentiation, and increase chemosensitization of tumor cells. Currently, there are five HDAC inhibitors (HDACi) approved by the U.S. Food and Drug Administration (FDA) or European Medicines Agency: vorinostat, romidepsin, belinostat, and panobinostat for the treatment of T-cell lymphoma or multiple myeloma as well as givinostat for treatment of Duchenne muscular dystrophy. Although the human genome encodes for more than 600 E3 ligases, only a few are predominately used in PROTAC development. For HDAC degradation, this is further limited to cereblon (CRBN), Von Hippel-Lindau (VHL), and cellular inhibitor of apoptosis proteins (cIAP). To fully harness the potential of PROTACs, the range of utilized E3 ligases needs to be expanded. As expression levels and activity of certain E3 ligases are tissue-or cell-type dependent, identifying and using new E3 ligases could enable the development of tissue specific PROTACs with reduced side effects. Likewise, targeting tumor-enriched or tumor-essential E3 ligases presents a promising opportunity to expand the range of E3 ligases employed, further enhancing the therapeutic potential of PROTACs in oncology. In addition, the most commonly used ligands for CRBN and VHL have certain limitations: thalidomide and derivatives are associated with teratogenicity and stability concerns, while VHL ligands tend to increase molecular weight and total polar surface area, which can create challenges for oral bioavailability and application. Furthermore, expanding the utilization of alternative E3 ligases can help to overcome cancer resistance against degraders. In fact, resistance mechanisms against PROTACs arise primarily at the CRL, but rarely at the POI, as they heavily rely on a multi-protein complex for successful degradation. Studies have shown that PROTACs can restore POI degradation in PROTAC-resistant cells by changing the recruited E3 ligase from CRBN to VHL. This highlights the importance of expanding the repertoire of E3 ligases used in TPD.