Targeted protein degradation (TPD) has reshaped modern pharmacology by shifting therapeutic strategies from occupancy-driven inhibition toward event-driven elimination of disease-causing proteins, including targets long regarded as undruggable. Beyond canonical modalities such as proteolysis-targeting chimeras and molecular glues, the TPD landscape has rapidly expanded to encompass diverse molecular scaffolds—including small molecules, antibodies, peptides, and nucleic acids—as well as multiple degradation pathways spanning the ubiquitin–proteasome system, lysosomal routes, and autophagy. This growing mechanistic and structural diversity has created an urgent need for an integrative framework to rationalize platform selection and translational potential. Here, we introduce a two-dimensional classification matrix that organizes TPD strategies according to degrader scaffold and degradation mechanism, revealing mechanistic “white spaces” that may represent underexplored opportunities for future TPD development. We further propose the TPDS analytical framework—encompassing Target class broadening, Platform refinement, Degradation mechanism reprogramming, and Scaffold expansion—to systematically map over 30 emerging TPD platforms. Finally, we discuss areas of clinical maturity in TPD, with representative examples from hematologic, hormone-driven, and kinase-driven malignancies, as well as key translational bottlenecks and emerging solutions, ranging from delivery engineering to AI-assisted degrader design. Together, these insights provide a strategic roadmap for the rational development of next-generation TPD therapeutics in precision oncology.