Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy to selectively remove disease-associated proteins. Unlike conventional small-molecule inhibitors, TPD can target proteins with modest interactions, expanding the range of druggable targets. The first-generation TPD approach, PROteolysis-TArgeting Chimeras (PROTACs), uses E3 ubiquitin ligases to induce polyubiquitination and proteasomal degradation. However, alternative TPD strategies, such as Molecular Glue Degraders (MGDs), have emerged, which do not rely on E3 ubiquitin ligases. These approaches offer unique advantages, particularly for targeting pathologic proteins on the cell membrane and in the extracellular space. This review focuses on direct lysosome- and proteasome-engaging modalities of TPD, including Autophagy-Tethering Compounds (ATTECs), AutOPhagy-Targeting Chimeras (AUTOTACs), Lysosome-Targeting Chimeras (LYTACs), and CytoKine receptor-Targeting Chimeras (KineTACs). These methods exploit the autophagy-lysosome system, which is activated under cellular stress, to degrade proteins, including those that are aggregation-prone or located in the extracellular space. ATTECs bind to LC3, a key component of autophagosome biogenesis, and target proteins for autophagic degradation. AUTOTACs interact with SQSTM1/p62, an autophagic receptor, to promote the degradation of misfolded proteins. LYTACs use glycopeptides to bind to the cation-independent mannose-6-phosphate receptor (CI-M6PR) or the asialoglycoprotein receptor (ASGPR) to target proteins for lysosomal degradation. KineTACs utilize cytokine receptors to trigger lysosomal degradation of membrane proteins. These alternative TPD approaches not only complement PROTACs but also offer unique strategies for targeting a broader range of proteins, including those involved in neurodegenerative diseases, cancer, and other pathologies. The review highlights the chemical and biological characteristics of each degrader, their advantages, and limitations, providing a comprehensive overview of the current state of TPD technology.Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy to selectively remove disease-associated proteins. Unlike conventional small-molecule inhibitors, TPD can target proteins with modest interactions, expanding the range of druggable targets. The first-generation TPD approach, PROteolysis-TArgeting Chimeras (PROTACs), uses E3 ubiquitin ligases to induce polyubiquitination and proteasomal degradation. However, alternative TPD strategies, such as Molecular Glue Degraders (MGDs), have emerged, which do not rely on E3 ubiquitin ligases. These approaches offer unique advantages, particularly for targeting pathologic proteins on the cell membrane and in the extracellular space. This review focuses on direct lysosome- and proteasome-engaging modalities of TPD, including Autophagy-Tethering Compounds (ATTECs), AutOPhagy-Targeting Chimeras (AUTOTACs), Lysosome-Targeting Chimeras (LYTACs), and CytoKine receptor-Targeting Chimeras (KineTACs). These methods exploit the autophagy-lysosome system, which is activated under cellular stress, to degrade proteins, including those that are aggregation-prone or located in the extracellular space. ATTECs bind to LC3, a key component of autophagosome biogenesis, and target proteins for autophagic degradation. AUTOTACs interact with SQSTM1/p62, an autophagic receptor, to promote the degradation of misfolded proteins. LYTACs use glycopeptides to bind to the cation-independent mannose-6-phosphate receptor (CI-M6PR) or the asialoglycoprotein receptor (ASGPR) to target proteins for lysosomal degradation. KineTACs utilize cytokine receptors to trigger lysosomal degradation of membrane proteins. These alternative TPD approaches not only complement PROTACs but also offer unique strategies for targeting a broader range of proteins, including those involved in neurodegenerative diseases, cancer, and other pathologies. The review highlights the chemical and biological characteristics of each degrader, their advantages, and limitations, providing a comprehensive overview of the current state of TPD technology.