The study introduces *DrugMap*, an atlas of cysteine ligandability across 416 cancer cell lines, which reveals significant heterogeneity in cysteine targeting. This heterogeneity is influenced by cellular redox states, protein conformational changes, and genetic mutations. The authors identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands. The NFκB1 probe blocks DNA binding, while the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. The findings provide a roadmap for systematic cysteine ligand discovery and drug development in oncology.The study introduces *DrugMap*, an atlas of cysteine ligandability across 416 cancer cell lines, which reveals significant heterogeneity in cysteine targeting. This heterogeneity is influenced by cellular redox states, protein conformational changes, and genetic mutations. The authors identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands. The NFκB1 probe blocks DNA binding, while the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. The findings provide a roadmap for systematic cysteine ligand discovery and drug development in oncology.