The human genome encodes approximately 20,000 proteins, of which about 85% lack well-defined druggable binding pockets, leaving most of the disease-relevant proteins “undruggable”. Small-molecule chemical probes are essential for modulating protein function and serve as leads for therapeutic development. However, the majority of the human proteome is inaccessible to conventional drug-like molecules due to the absence of suitable binding pockets. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are considered undruggable. The IDPs play key roles in transcriptional regulation, oncogenic signaling, and cellular stress responses even though they lack stable tertiary structures. Cysteine chemoproteomics has become a promising approach to address this druggability gap by mapping cysteine reactivity across the proteome.  Cysteine-thiol (Cys-SH) is often considered the most suitable nucleophile for site-selective protein modification due to its high intrinsic reactivity and low natural abundance. However, this approach also has significant challenges because the conventional cysteine-targeted electrophiles (warheads) mainly modify solvent-exposed residues in well-folded structured domains of proteins. Thereby making IDPs and IDRs largely inaccessible for covalent targeting. There are currently available strategies for targeting IDPs, but they often rely on serendipitous or cryptic pocket targeting. To address these challenges, this work combines multiple disciplines like structure-guided design, chemical synthesis, analytical characterization, quantitative mass spectrometry-based chemoproteomics, computational modeling, structural data integration, and cell-based validation. Our main hypothesis was that cyclometalated Au(III)[C^N] frameworks bearing unconventional and tunable bulky monodentate phosphine ancillary ligands would control the steric shielding at the gold(III) center to enable site-selective cysteine arylation within disordered regions of proteins. These gold(III) complexes form irreversible C(sp²)- bonds with Cys-SH via metal-mediated aryl transfer. The square-planar geometry of these gold(III) complexes and gold’s relativistic effect enhance their electrophilicity and affinity for soft nucleophiles like Cys-SH. Altogether, we designed a next-generation biorthogonal cyclometalated gold(III) probe platform and expanded our in-house technique named “Metal-mediated Ligand Affinity Chemistry (MLAC)” by conjugating protein-binding ligands to gold(III) arylating reagents for proximity-driven, site-selective covalent modification of native IDPs. We demonstrated covalent targeting of historically undruggable proteins, achieving a "speed + IDP selectivity" profile which is  unreachable for conventional electrophiles. We profiled the human cysteinome in triple-negative breast cancer (TNBC) cell lines through gold(III)-mediated one-pot CuAAC biorthogonal click chemistry using quantitative chemoproteomics. This approach identified 391 IDPs, including 261 undruggable proteins that are not targeted by FDA-approved drugs or small molecules listed in DrugBank or ChEMBL. However, the impact of our MLAC work will be limited if researchers in the field cannot apply this platform in biologically relevant systems. Using this platform, we developed gold(III) arylating reagents conjugated to Lenalidomide to selectively target cysteines coordinated to the zinc(II) metal center in Cereblon to reprogram the specificity of E3 ligases and expand the degradable proteome. We further extended this chemistry towards therapeutic translation studies to engineer site-specific antibody-drug conjugates (ADCs) with enhanced homogeneity and drug-to-antibody ratio (DAR) while preserving antibody activity. Collectively, this dissertation expands our understanding of the druggable cysteinome by establishing cyclometalated gold(III) chemistry as a unique framework for IDP targeting and quantitative chemoproteomic mapping. Also, this work provides insights on structure-guided principles of gold(III) probe design and mass spectrometry-based workflows that enable covalent targeting of proteins previously considered undruggable.