The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy, particularly for targeting proteins previously considered "undruggable." Thalidomide analogs, used in multiple myeloma treatment, serve as prime examples, acting as molecular glues to redirect the CRBN E3 ubiquitin ligase to degrade myeloma-dependency factors, IKZF1 and IKZF3. The clinical success of these analogs highlights the therapeutic potential of induced protein degradation. Beyond molecular glue degraders, other modalities such as heterobifunctional degraders, polymerization-induced degradation, ligand-dependent degradation of nuclear hormone receptors, and disruption of protein interactions are being developed and evaluated in clinical trials. This review provides an overview of various degradation modalities, their clinical applications, and future directions in the field of protein degradation. Key mechanisms include the formation of new surfaces between substrate and E3 ligase, drug-induced changes in protein state, and indirect regulation of endogenous degradation pathways. The field is rapidly advancing, driven by technological progress in proteomics, genetic screening, biochemical assays, and structural biology, offering new opportunities for expanding the druggability of previously intractable disease-modifying protein targets.The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy, particularly for targeting proteins previously considered "undruggable." Thalidomide analogs, used in multiple myeloma treatment, serve as prime examples, acting as molecular glues to redirect the CRBN E3 ubiquitin ligase to degrade myeloma-dependency factors, IKZF1 and IKZF3. The clinical success of these analogs highlights the therapeutic potential of induced protein degradation. Beyond molecular glue degraders, other modalities such as heterobifunctional degraders, polymerization-induced degradation, ligand-dependent degradation of nuclear hormone receptors, and disruption of protein interactions are being developed and evaluated in clinical trials. This review provides an overview of various degradation modalities, their clinical applications, and future directions in the field of protein degradation. Key mechanisms include the formation of new surfaces between substrate and E3 ligase, drug-induced changes in protein state, and indirect regulation of endogenous degradation pathways. The field is rapidly advancing, driven by technological progress in proteomics, genetic screening, biochemical assays, and structural biology, offering new opportunities for expanding the druggability of previously intractable disease-modifying protein targets.