The article reviews the past two decades of targeted protein degradation (TPD) research, focusing on the development and clinical progress of proteolysis-targeting chimeras (PROTACs). PROTACs are heterobifunctional small molecules that recruit both a target protein (POI) and an E3 ubiquitin ligase, leading to the ubiquitylation and degradation of the POI. The article highlights the transition of TPD from academia to industry, with numerous companies advancing PROTAC programs in preclinical and early clinical stages. Key milestones include the first clinical trials of PROTACs targeting the androgen receptor (AR) and estrogen receptor (ER) in 2019, followed by positive clinical data in 2020. The review also discusses the potential of TPD to address previously 'undruggable' targets and the future directions for the field, including expanding the use of ubiquitin ligases, extending TPD beyond oncology, and exploring alternative degrader approaches such as autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), lysosome-targeting chimeras (LYTACs), and antibody-based PROTACs (AbTACs). The authors emphasize the importance of understanding the PROTACability of targets and the need to identify new E3 ligases for more effective and versatile TPD therapies.The article reviews the past two decades of targeted protein degradation (TPD) research, focusing on the development and clinical progress of proteolysis-targeting chimeras (PROTACs). PROTACs are heterobifunctional small molecules that recruit both a target protein (POI) and an E3 ubiquitin ligase, leading to the ubiquitylation and degradation of the POI. The article highlights the transition of TPD from academia to industry, with numerous companies advancing PROTAC programs in preclinical and early clinical stages. Key milestones include the first clinical trials of PROTACs targeting the androgen receptor (AR) and estrogen receptor (ER) in 2019, followed by positive clinical data in 2020. The review also discusses the potential of TPD to address previously 'undruggable' targets and the future directions for the field, including expanding the use of ubiquitin ligases, extending TPD beyond oncology, and exploring alternative degrader approaches such as autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), lysosome-targeting chimeras (LYTACs), and antibody-based PROTACs (AbTACs). The authors emphasize the importance of understanding the PROTACability of targets and the need to identify new E3 ligases for more effective and versatile TPD therapies.