The water-gas shift reaction (WGSR) is an important reaction system and can be applied for removing small amounts of CO from H2-rich gases for polymer electrolyte membrane fuel cells. However, the mechanism of the reaction is still in dispute. In order to clarify the mechanism of WGSR, the detailed mechanisms of WGSR on a series of binary clusters Cu6TM (TM=Co, Rh, Ir, Ni, Pd, Pt, Ag, Au) were investigated by density functional theory, using the PBE functional along with the Lanl2dz basis for metals and 6-311++G(d,p) for non-metals in this paper. The computational results indicated that the absorption of CO molecules on Cu6TM is easier than that of H2O. WGSR mechanism involves the redox, carboxyl and formate pathways, which correspond to CO*+O*→CO2(g), CO*+OH*→COOH*→CO2(g)+H*, and CO*+H*+O*→CHO*+O*→HCOO**→CO2(g)+H*, respectively. The experimentally most observed formate can be attributed to its lower formation and higher dissociation barriers. And dopant Co, Rh, Ni and Pd on copper cluster can have more beneficial effects than pure copper on the catalytic activity. Furthermore, the role of formate, a spectator or key intermediate, on Cu6TM (TM=Co, Rh, Ni, Pd) surfaces has been investigated. WGSR activity has been determined from the initial CO consumption and final CO2 product rates. The calculation results show that WGSR is mostly follows the redox pathway on Cu6TM (TM=Ni, Pd) surface due to the lower CO oxidation barriers; on the other hand, all the three pathways contribute similarly in WGSR on Cu6TM (TM=Co, Rh) surfaces. The results can help us to understand the catalytic behavior in experiment, design better catalysts, and, therefore, move one step forward to enable hydrogen economy to the practical application.