Targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are becoming a widespread source of chemical probes and lead compounds that degrade rather than inhibit target proteins, providing a different drug modality with potential to expand the "druggable" proteome. These chimeric molecules typically contain a protein-of-interest (POI)targeting ligand (or warhead) and a ligand which binds to an E3 ligase, connected by a linker. PROTAC-induced ternary complexes between the POI and E3 ligase are required for polyubiquitination and targeted degradation of the POI. PROTACs do not require full target occupancy, because a single PROTAC molecule can induce degradation of more than one target protein molecule over time, thereby acting catalytically at sub-stoichiometric target occupancy. These distinct features of PROTACs mode of action have been shown to result in increased target selectivity, higher potencies, and fewer off-target effects compared to small molecule inhibitors. Furthermore, unlike small molecule inhibitors, PROTACs can bind the target at any position, including non-functional binding sites. Notably, PROTACs have shown to be developable for use in humans, with several compounds reaching the clinic, including ARV-110 and ARV-471 that have recently progressed into Phase II clinical trials for prostate and breast cancer, respectively, demonstrating both safety and efficacy in patients. While PROTACs harbor several advantages as a new modality within drug discovery, their bifunctional nature and chemical composition mean that they are inherently larger than the warhead ligands on which they are based. This makes PROTAC compounds go beyond the "Rule of 5" (bRo5), and can impose hurdles to their pharmaceutical development. Thus, efforts have been made recently to better understand the physicochemical properties and structure-property relationships of PROTACs in order to identify design parameters that may help guide development in this chemical space. An important pharmacokinetic hurdle for high molecular weight compounds tends to be permeability. Uptake into cells occurs in competition with efflux, which is also commonly a problem for large molecules. Indeed, recently we and others have established that PROTACs can show potent cellular activity despite exhibiting very low permeabilities compared to their individual ligand components and to more conventional inhibitors. There is therefore a great interest to develop strategies for improving cell permeability and other physicochemical properties of PROTACs.