With the discovery of PROteolysis TArgeting Chimeras (PROTACs) twenty years ago, targeted protein degradation (TPD) has changed the landscape of drug development. PROTACs have evolved from cell-impermeable peptide-small molecule chimeras to orally bioavailable clinical candidate drugs that degrade oncogenic proteins in humans. As we move into the third decade of TPD, the pace of discovery will only accelerate. Improved technologies are enabling the development of ligands for “undruggable” proteins and the recruitment of new E3 ligases. Moreover, enhanced computing power will expedite identification of active degraders. Here we discuss the strides made in these areas and what advances we can look forward to as the next decade in this exciting field begins.