Targeted Protein degraders (TPDs) show promise in harnessing cellular machinery to eliminate disease-causing proteins, even those previously considered undruggable. Especially if protein turnover is low, targeted protein removal bestows lasting therapeutic effect over typical inhibition. The demonstrated safety and efficacy profile of clinical candidates has fueled the surge in the number of potential candidates across different therapeutic areas. As TPDs often do not comply with Lipinski's rule of five, developing novel TPDs and unlocking their full potential requires overcoming solubility, permeability and oral bioavailability challenges. Tailored in-vitro assays are key to precise profiling and optimization, propelling breakthroughs in targeted protein degradation.