Targeted protein degradation (TPD) has emerged as a promising strategy for selectively removing disease-associated proteins. Unlike conventional inhibitors, TPD can operate through modest interactions between target proteins and binding molecules. The first-generation TPD approach, PROTACs, uses synthetic heterobifunctional compounds that bind to a target protein and recruit an E3 ubiquitin ligase. This leads to the ubiquitination and degradation of the target protein by the proteasome. Molecular glue degraders (MGDs) share a similar mechanism but lack the linker element and can offer pharmacological advantages over PROTACs. Recent advancements in TPD have focused on alternative strategies that do not rely on ubiquitination. These include autophagy-mediated degradation, which utilizes the autophagy-lysosome system to degrade intracellular proteins and organelles. Autophagy is an inducible system that becomes active under cellular stress, such as nutrient starvation or pathogen infection. It can degrade non-proteinaceous entities, including nucleic acids, pathogens, and organelles. The autophagy process involves the formation of autophagosomes, which fuse with lysosomes to degrade the cargo. Several TPD technologies have been developed to exploit the autophagy-lysosome system. For example, AuTophagy-TEthering Compounds (ATTECs) use LC3 ligands to target autophagosomes and degrade intracellular proteins. These compounds have shown effectiveness in reducing pathologic proteins such as mutant huntingtin in cell and animal models. Another approach, AUTOphagy-TArgeting Chimera (AUTOTAC), uses SQSTM1/p62 receptors to target autophagosomes and degrade specific proteins. These degraders have demonstrated the ability to target a wide range of cellular components, including proteins and organelles. In addition to autophagy, other TPD strategies have been developed to target secreted and membrane proteins through the endolysosomal pathway. LYTACs utilize the cation-independent mannose-6-phosphate receptor (CI-M6PR) to target extracellular proteins and facilitate their lysosomal degradation. These compounds have shown effectiveness in degrading proteins such as apolipoprotein E4 and epidermal growth factor receptor (EGFR). Similarly, integrin-facilitated lysosomal degradation (IFLD) and dendronized DNA chimera (DENTAC) use integrins and scavenger receptors to target extracellular and membrane-associated proteins. These TPD strategies offer unique advantages over traditional PROTACs, including the ability to degrade a broader range of proteins and organelles. However, challenges remain in optimizing their pharmacological profiles and ensuring their safety and efficacy. Continued research and development are needed to refine these technologies and expand their therapeutic applications.Targeted protein degradation (TPD) has emerged as a promising strategy for selectively removing disease-associated proteins. Unlike conventional inhibitors, TPD can operate through modest interactions between target proteins and binding molecules. The first-generation TPD approach, PROTACs, uses synthetic heterobifunctional compounds that bind to a target protein and recruit an E3 ubiquitin ligase. This leads to the ubiquitination and degradation of the target protein by the proteasome. Molecular glue degraders (MGDs) share a similar mechanism but lack the linker element and can offer pharmacological advantages over PROTACs. Recent advancements in TPD have focused on alternative strategies that do not rely on ubiquitination. These include autophagy-mediated degradation, which utilizes the autophagy-lysosome system to degrade intracellular proteins and organelles. Autophagy is an inducible system that becomes active under cellular stress, such as nutrient starvation or pathogen infection. It can degrade non-proteinaceous entities, including nucleic acids, pathogens, and organelles. The autophagy process involves the formation of autophagosomes, which fuse with lysosomes to degrade the cargo. Several TPD technologies have been developed to exploit the autophagy-lysosome system. For example, AuTophagy-TEthering Compounds (ATTECs) use LC3 ligands to target autophagosomes and degrade intracellular proteins. These compounds have shown effectiveness in reducing pathologic proteins such as mutant huntingtin in cell and animal models. Another approach, AUTOphagy-TArgeting Chimera (AUTOTAC), uses SQSTM1/p62 receptors to target autophagosomes and degrade specific proteins. These degraders have demonstrated the ability to target a wide range of cellular components, including proteins and organelles. In addition to autophagy, other TPD strategies have been developed to target secreted and membrane proteins through the endolysosomal pathway. LYTACs utilize the cation-independent mannose-6-phosphate receptor (CI-M6PR) to target extracellular proteins and facilitate their lysosomal degradation. These compounds have shown effectiveness in degrading proteins such as apolipoprotein E4 and epidermal growth factor receptor (EGFR). Similarly, integrin-facilitated lysosomal degradation (IFLD) and dendronized DNA chimera (DENTAC) use integrins and scavenger receptors to target extracellular and membrane-associated proteins. These TPD strategies offer unique advantages over traditional PROTACs, including the ability to degrade a broader range of proteins and organelles. However, challenges remain in optimizing their pharmacological profiles and ensuring their safety and efficacy. Continued research and development are needed to refine these technologies and expand their therapeutic applications.