The ubiquitin (Ub)-proteasome system (UPS) is a key mechanism for protein turnover in eukaryotic cells, mediating the degradation of unwanted or damaged proteins. Recent advancements in UPS-based technologies, including molecular glue degraders, PROTACs (proteolysis-targeting chimeras), and DUBTACs (deubiquitinase-targeting chimeras), have enabled targeted protein degradation or stabilization. Molecular glue degraders and PROTACs induce interactions between Ub ligases and target proteins, leading to their degradation via the UPS. DUBTACs, on the other hand, enhance protein stability by deubiquitinating target proteins. These technologies have shown promise in targeting disease-related proteins, particularly in cancer therapy. Thalidomide and its derivatives, such as lenalidomide and pomalidomide, are examples of molecular glue degraders that target the cereblon (CRBN) protein, leading to the degradation of specific substrates like IKZF1 and IKZF3. Aryl sulfonamides, such as indisulam and E7820, also act as molecular glue degraders by targeting DCAF15 and stabilizing proteins involved in mRNA splicing. Cyclin-dependent kinase (CDK) inhibitors, like CR8 and dCEMM2, have been developed as molecular glue degraders that target CDK12 and CDK13. PROTACs are heterobifunctional molecules that bind to target proteins and Ub ligases, promoting their degradation. They have been used to target proteins like EGFR and ALK, with some variants being light-activated (opto-PROTACs). DUBTACs stabilize proteins by deubiquitinating them, which is particularly useful in diseases like cystic fibrosis where the ΔF508-CFTR mutant is misfolded. Despite their potential, challenges remain, including the need for more specific ligands and the risk of drug resistance. Future research aims to expand the applications of these technologies, improve their safety, and develop more effective therapies for undruggable disease targets.The ubiquitin (Ub)-proteasome system (UPS) is a key mechanism for protein turnover in eukaryotic cells, mediating the degradation of unwanted or damaged proteins. Recent advancements in UPS-based technologies, including molecular glue degraders, PROTACs (proteolysis-targeting chimeras), and DUBTACs (deubiquitinase-targeting chimeras), have enabled targeted protein degradation or stabilization. Molecular glue degraders and PROTACs induce interactions between Ub ligases and target proteins, leading to their degradation via the UPS. DUBTACs, on the other hand, enhance protein stability by deubiquitinating target proteins. These technologies have shown promise in targeting disease-related proteins, particularly in cancer therapy. Thalidomide and its derivatives, such as lenalidomide and pomalidomide, are examples of molecular glue degraders that target the cereblon (CRBN) protein, leading to the degradation of specific substrates like IKZF1 and IKZF3. Aryl sulfonamides, such as indisulam and E7820, also act as molecular glue degraders by targeting DCAF15 and stabilizing proteins involved in mRNA splicing. Cyclin-dependent kinase (CDK) inhibitors, like CR8 and dCEMM2, have been developed as molecular glue degraders that target CDK12 and CDK13. PROTACs are heterobifunctional molecules that bind to target proteins and Ub ligases, promoting their degradation. They have been used to target proteins like EGFR and ALK, with some variants being light-activated (opto-PROTACs). DUBTACs stabilize proteins by deubiquitinating them, which is particularly useful in diseases like cystic fibrosis where the ΔF508-CFTR mutant is misfolded. Despite their potential, challenges remain, including the need for more specific ligands and the risk of drug resistance. Future research aims to expand the applications of these technologies, improve their safety, and develop more effective therapies for undruggable disease targets.