ABSTRACT Targeted protein degradation (TPD) represents a paradigm shift in drug discovery, moving beyond traditional binding‐based inhibition toward active removal of disease‐driving proteins. This approach has unlocked therapeutic possibilities for previously “undruggable” targets, including transcription factors like MYC and STAT3, mutant oncoproteins such as KRAS G12C, and scaffolding molecules lacking conventional binding pockets. Among TPD strategies, proteolysis‐targeting chimeras (PROTACs) have emerged as the leading clinical platform, with the first molecule entering trials in 2019 and progression to Phase III completion by 2024. This comprehensive review examines PROTAC development across diverse therapeutic areas, analyzing key targets including kinases, hormone receptors, antiapoptotic proteins, and epigenetic modulators. We evaluate clinical progression of breakthrough candidates such as ARV‐110 for prostate cancer, ARV‐471 for breast cancer, and BTK degraders, while discussing critical challenges including the “hook effect” and oral bioavailability limitations. The review explores future directions encompassing innovative delivery strategies, tissue‐specific degrader design, and approaches for expanding E3 ligase repertoires and overcoming resistance. This review provides essential foundations for rational target selection, molecular optimization, and clinical translation strategies. By integrating mechanistic insights with clinical realities, this analysis offers perspectives on PROTAC technology advancement and identifies opportunities for transforming treatment of complex diseases resistant to conventional therapies.