Oxidation of CO into CO2 is a prototypical reaction in heterogeneous catalysis and is one of the extensively studied reactions in the gas phase to explore the underlying mechanisms of related catalysis. In this Feature Article, we present and discuss our recent advances in the fundamental understanding of catalytic CO oxidation by O2 mediated with heteronuclear metal oxide clusters (HMOCs) using state-of-the-art mass spectrometry and quantum chemistry calculations. The HMOCs can be considered as ideal models for active sites on mixed or oxide supported catalysts at a strictly molecular level. A concept of electronegativity-ladder effect was proposed to account for the enhanced reactivity of noble metal (NM) doped HMOCs, and then this effect was successfully extended in the design of NM-free HMOCs in catalytic CO oxidation by O2. The future directions and the challenges were also discussed.