This work is dedicated to the memory and achievements of Dr. Haldor Topsøe.Keywords: H/D substitution Methanol Copper Reverse water gas shift DFT Kinetics Mechanism CO 2 hydrogenation a b s t r a c t H/D exchange experiments on a Cu/ZnO/Al 2 O 3 catalyst have shown that methanol synthesis and RWGS display a strong thermodynamic isotope effect, which is attributed to differences in the zero-point energy of hydrogenated vs. deuterated species. The effect is larger for methanol synthesis and substantially increases the equilibrium yield in deuterated syngas. In the kinetic regime of CO 2 hydrogenation, an inverse kinetic isotope effect of H/D substitution was observed, which is stronger for methanol synthesis than for CO formation suggesting that the two reactions do not share a common intermediate. Similar observations were also made on other catalysts such as Cu/MgO, Cu/SiO 2 , and Pd/SiO 2 . In contrast to CO 2 hydrogenation, the CO hydrogenation on Cu/ZnO/Al 2 O 3 did not show such a strong kinetic isotope effect indicating that methanol formation from CO 2 does not proceed via consecutive reverse water gas shift and CO hydrogenation steps. The inverse KIE is consistent with formate hydrogenation being the rate-determining step of methanol synthesis from CO 2 . Differences in the extent of product inhibition by water, observed for methanol synthesis and reverse water gas shift indicate that the two reactions proceed on different surface sites in a parallel manner. The consequences for catalyst design for effective methanol synthesis from CO 2 are discussed.