The effect of S-acetylation in MN₂S₂ complexes on metal exchange reactivity was examined in a series of MN₂S₂O₂ complexes. While clean exchange processes do not occur for the MN₂S₂ derivatives where formation of S-bridged aggregates predominate, acetylation permits the metal exchange with hierarchy that follows the Irving–Williams series of stability for first row transition metals: Fe²⁺ < Co²⁺ < Ni²⁺ < Cu²⁺ > Zn²⁺. The rate determining step consistent with kinetic parameters depends on both M and M′, supporting a mechanism of exchange that involves ligand unwrapping/rewrapping process as earlier defined by Margerum et al. for M(EDTA) systems. The enhanced metal exchange deriving from S-acetylation is of significance to probes and detection of cysteine-S metallo-proteins and metallo-enzyme active sites, and highlights a new role for S-acetylation.