The article discusses the emerging paradigm of induced protein degradation as an alternative approach to traditional small-molecule drug discovery. Traditional methods often target proteins with binding sites that directly affect protein function, but this approach can be limited by the lack of suitable binding pockets and may require high systemic drug exposures to achieve sufficient target inhibition, increasing the risk of off-target effects. Induced protein degradation, on the other hand, is an 'event-driven' approach where the target protein is tagged for elimination upon drug binding. This method offers several advantages, including reduced systemic drug exposure, the ability to counteract increased target protein expression, and the potential to target proteins that are not currently therapeutically tractable, such as transcription factors and scaffolding proteins. The article highlights the development of technologies like proteolysis-targeting chimeras (PROTACs) and hydrophobic tagging (HyT) that exploit cellular quality control mechanisms to selectively degrade target proteins. PROTACs, which combine a ligand for the target protein with an E3 ligase recruiting ligand, have shown promising results in preclinical models, demonstrating sub-stoichiometric activity and improved efficacy compared to traditional inhibitors. HyT, on the other hand, uses bifunctional molecules that bind to the target protein and recruit the E3 ligase, leading to protein degradation via the ubiquitin-proteasome system. The article also reviews the progress made in developing PROTACs, including the identification of potent small-molecule ligands for E3 ligases and the demonstration of their efficacy in cell culture and mouse models. It discusses the challenges and opportunities in the field, such as the need for further optimization of PROTACs to improve potency and selectivity, and the potential for tissue-specific or disease-specific degradation using tissue/disease-specific E3 ligases. Overall, the article emphasizes the potential of induced protein degradation as a novel drug discovery paradigm, highlighting its advantages over traditional methods and the ongoing efforts to develop it into a viable therapeutic strategy.The article discusses the emerging paradigm of induced protein degradation as an alternative approach to traditional small-molecule drug discovery. Traditional methods often target proteins with binding sites that directly affect protein function, but this approach can be limited by the lack of suitable binding pockets and may require high systemic drug exposures to achieve sufficient target inhibition, increasing the risk of off-target effects. Induced protein degradation, on the other hand, is an 'event-driven' approach where the target protein is tagged for elimination upon drug binding. This method offers several advantages, including reduced systemic drug exposure, the ability to counteract increased target protein expression, and the potential to target proteins that are not currently therapeutically tractable, such as transcription factors and scaffolding proteins. The article highlights the development of technologies like proteolysis-targeting chimeras (PROTACs) and hydrophobic tagging (HyT) that exploit cellular quality control mechanisms to selectively degrade target proteins. PROTACs, which combine a ligand for the target protein with an E3 ligase recruiting ligand, have shown promising results in preclinical models, demonstrating sub-stoichiometric activity and improved efficacy compared to traditional inhibitors. HyT, on the other hand, uses bifunctional molecules that bind to the target protein and recruit the E3 ligase, leading to protein degradation via the ubiquitin-proteasome system. The article also reviews the progress made in developing PROTACs, including the identification of potent small-molecule ligands for E3 ligases and the demonstration of their efficacy in cell culture and mouse models. It discusses the challenges and opportunities in the field, such as the need for further optimization of PROTACs to improve potency and selectivity, and the potential for tissue-specific or disease-specific degradation using tissue/disease-specific E3 ligases. Overall, the article emphasizes the potential of induced protein degradation as a novel drug discovery paradigm, highlighting its advantages over traditional methods and the ongoing efforts to develop it into a viable therapeutic strategy.