For many applications of well-defined gold nano-clusters, it is desirable to understand their structural evolution behavior under working conditions with molecular precision. Here we report the first systematic investigation of the size transformation products of the Au-22(SG)(18) nanocluster under representative working conditions and highlight the surface effect on the transformation kinetics. Under thermal and aerobic conditions, the consecutive and pH-dependent transformation from Au(22 )to both well-defined clusters and small Au(I)SR species was identified by ESI-MS and UV-vis spectroscopy. By introducing a perturbation onto the Au-22 surface, significant changes in the activation parameters were determined from the kinetic study of the Au-22 transformation. This indicates the sensitivity of the nanocluster transformation pathway to the cluster surface. The systematic study of cluster transformation and the sensitivity of cluster transformation to the surface revealed herein has significant implications for future attempts to design gold nanoparticles with adaptation to the working environment and the regeneration of active nanoparticles.