Traditional occupancy-driven pharmacology and emerging event-driven targeted protein degradation (TPD) play distinct roles in drug discovery. Although small-molecule inhibitors typically depend on sustained engagement of functional binding and often require systemic exposure, TPD induces selective protein elimination and can access targets that are refractory to conventional inhibition, namely, "undruggable" proteins. Expanding degradation mechanisms mediated by the ubiquitin‒proteasome system (UPS) and alternative pathways is therefore a central strategy for next-generation therapeutics. In this review, we provide an overview of the developmental trajectory of the TPD field and discuss how diverse modalities can be leveraged to address intracellular, membrane-associated, and extracellular protein targets. We summarize the relevant chemical design principles and translational challenges, with a focus on mitigating off-target toxicity, improving selectivity, and increasing bioavailability. The current evidence suggests that proteolysis-targeting chimeras, molecular glues, autophagy-targeting chimeras, and transferrin receptor-targeting chimeras could be key approaches. In addition, we discuss some innovative discovery platforms for expanding E3 ligase repertoires that may enable more rational degrader design. Finally, we highlight the current landscape of clinical trials and discuss opportunities and remaining hurdles for advancing TPD toward clinical translation.
