Finding a replacement for the toxic hexavalent chromium oxide in commercial iron oxide-based high temperature water-gas shift (HT-WGS) catalyst is of current environmental concern. Previous studies in developing Cr-free catalysts mainly focus on ex-situ characterization on catalysts bulk structure. In the present study, CuO/MOx-Fe2O3 catalysts promoted by Si, Al, Cr or Mg were studied with XRD, in situ Raman, HS-LEIS, BET, transient (CO2)-O-16 -> (CO2)-O-18 isotopic switch, steady-state WGS 'activity test and CO-TPR to elucidate their structure-activity relationships. The Mg and Al are homogeneously distributed within both fresh and activated catalysts as texture promoters, while the Si exists as discrete SiO2 that is covered by iron oxides. During the HT-WGS reaction, the Mg promoter resulted in the poorest thermally stability and least amount of metal-metal oxide interface, and the Si promoter inhibited the reducibility of surface oxygen. Only the Al promoter was found to yield a catalyst that possessed similar catalyst structure, comparable thermostability and activity with the Cr-promoted catalyst. This work demonstrates the importance of in situ characterization to the rational design of Cr-free iron oxide based HT-WGS catalysts.