Cysteine sulfenic acid (SOH) modifications are pivotal in redox signaling, yet establishing their causal biological roles remains challenging due to methodological limitations. Traditional approaches often lack precision or disrupt non-redox cysteine functions. This perspective highlights two innovative chemical biology strategies to address these challenges: (1) integrating bioorthogonal cleavage chemistry with genetic code expansion for site-specific SOH incorporation in proteins of interest, enabling controlled activation of redox events, and (2) developing redox-targeted covalent inhibitors (TCIs) to selectively block SOH modifications. By bridging technological innovation with mechanistic inquiry, these strategies not only help to elucidate SOH-mediated signaling networks for the better understanding of redox biology, but also hold therapeutic promise for precise redox medicine.
