DrugMap is a comprehensive atlas of cysteine ligandability across 416 cancer cell lines, revealing that cysteine reactivity varies significantly among cancers. This variation is influenced by cellular redox states, protein conformational changes, and genetic mutations. By analyzing these factors, researchers identified actionable cysteines in key oncogenic proteins such as NFκB1 and SOX10, and developed covalent ligands that disrupt their activity. The NFκB1 ligand blocks DNA binding, while the SOX10 ligand enhances protein-protein interactions, disrupting melanoma transcriptional signaling. DrugMap provides a framework for systematically understanding cysteine ligandability and developing covalent probes to target oncogenic transcription factors. The study highlights the importance of considering cellular redox states and protein conformational changes in drug development. It also demonstrates that mutations can influence cysteine ligandability, offering new opportunities for targeted therapy. The findings underscore the potential of cysteine-focused chemical proteomics in identifying novel therapeutic targets and understanding the complex dynamics of protein interactions in cancer. DrugMap serves as a valuable resource for oncology research, enabling the discovery of covalent ligands against challenging cancer targets.DrugMap is a comprehensive atlas of cysteine ligandability across 416 cancer cell lines, revealing that cysteine reactivity varies significantly among cancers. This variation is influenced by cellular redox states, protein conformational changes, and genetic mutations. By analyzing these factors, researchers identified actionable cysteines in key oncogenic proteins such as NFκB1 and SOX10, and developed covalent ligands that disrupt their activity. The NFκB1 ligand blocks DNA binding, while the SOX10 ligand enhances protein-protein interactions, disrupting melanoma transcriptional signaling. DrugMap provides a framework for systematically understanding cysteine ligandability and developing covalent probes to target oncogenic transcription factors. The study highlights the importance of considering cellular redox states and protein conformational changes in drug development. It also demonstrates that mutations can influence cysteine ligandability, offering new opportunities for targeted therapy. The findings underscore the potential of cysteine-focused chemical proteomics in identifying novel therapeutic targets and understanding the complex dynamics of protein interactions in cancer. DrugMap serves as a valuable resource for oncology research, enabling the discovery of covalent ligands against challenging cancer targets.