Targeted protein degradation (TPD) is an emerging therapeutic approach that enables the degradation of disease-causing proteins that have been difficult to target with conventional small molecules. The concept of proteolysis-targeting chimeras (PROTACs) was introduced in 2001, and since then, TPD has evolved from academic research to industrial development, with numerous companies now in preclinical and early clinical stages. In 2020, clinical proof-of-concept for PROTACs was achieved against two well-established cancer targets, the estrogen receptor (ER) and androgen receptor (AR), marking a significant milestone. The field is now poised to target previously 'undruggable' proteins. PROTACs are heterobifunctional molecules that consist of two ligands connected by a linker. One ligand binds a target protein (POI), while the other binds an E3 ubiquitin ligase. The PROTAC induces ubiquitylation of the POI, leading to its degradation by the ubiquitin-proteasome system (UPS). This mechanism distinguishes PROTACs from classical inhibitors, which have a one-to-one relationship with the POI and are driven by stoichiometry and interactions with catalytic sites. Other types of targeted protein degraders include molecular glues, which enhance protein-protein interactions to promote ubiquitylation. These include compounds like thalidomide and its analogues, which are known as immunomodulatory imide drugs (IMiDs). The development of PROTACs has progressed from peptide-based molecules to fully synthetic, rationally designed small molecules. The clinical translation of TPD has advanced significantly, with PROTACs like ARV-110 and ARV-471 entering clinical trials. ARV-110 targets the androgen receptor (AR) in prostate cancer, while ARV-471 targets the estrogen receptor (ER) in breast cancer. Both have shown promising results, with ARV-110 demonstrating degradation of the AR protein and antitumor activity. ARV-471 has also shown clinical efficacy in breast cancer patients. The future of TPD involves expanding the use of E3 ubiquitin ligases to enable precision medicine and extending the modality beyond oncology. The field is also exploring new E3 ligases and alternative degrader approaches, such as autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), lysosome-targeting chimeras (LYTACs), and antibody-based PROTACs (AbTACs). These approaches aim to degrade proteins through non-UPS pathways. The potential of TPD is vast, with the ability to target proteins that have been previously considered undruggable. The field is now at a critical juncture, with the opportunity to explore new E3 ligasesTargeted protein degradation (TPD) is an emerging therapeutic approach that enables the degradation of disease-causing proteins that have been difficult to target with conventional small molecules. The concept of proteolysis-targeting chimeras (PROTACs) was introduced in 2001, and since then, TPD has evolved from academic research to industrial development, with numerous companies now in preclinical and early clinical stages. In 2020, clinical proof-of-concept for PROTACs was achieved against two well-established cancer targets, the estrogen receptor (ER) and androgen receptor (AR), marking a significant milestone. The field is now poised to target previously 'undruggable' proteins. PROTACs are heterobifunctional molecules that consist of two ligands connected by a linker. One ligand binds a target protein (POI), while the other binds an E3 ubiquitin ligase. The PROTAC induces ubiquitylation of the POI, leading to its degradation by the ubiquitin-proteasome system (UPS). This mechanism distinguishes PROTACs from classical inhibitors, which have a one-to-one relationship with the POI and are driven by stoichiometry and interactions with catalytic sites. Other types of targeted protein degraders include molecular glues, which enhance protein-protein interactions to promote ubiquitylation. These include compounds like thalidomide and its analogues, which are known as immunomodulatory imide drugs (IMiDs). The development of PROTACs has progressed from peptide-based molecules to fully synthetic, rationally designed small molecules. The clinical translation of TPD has advanced significantly, with PROTACs like ARV-110 and ARV-471 entering clinical trials. ARV-110 targets the androgen receptor (AR) in prostate cancer, while ARV-471 targets the estrogen receptor (ER) in breast cancer. Both have shown promising results, with ARV-110 demonstrating degradation of the AR protein and antitumor activity. ARV-471 has also shown clinical efficacy in breast cancer patients. The future of TPD involves expanding the use of E3 ubiquitin ligases to enable precision medicine and extending the modality beyond oncology. The field is also exploring new E3 ligases and alternative degrader approaches, such as autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), lysosome-targeting chimeras (LYTACs), and antibody-based PROTACs (AbTACs). These approaches aim to degrade proteins through non-UPS pathways. The potential of TPD is vast, with the ability to target proteins that have been previously considered undruggable. The field is now at a critical juncture, with the opportunity to explore new E3 ligases