Quantum chemical and ab initio thermodynamic calculations were used to investigate the mechanism of CO oxidation on Au/TiO₂ and the geometric and electronic character of active sites. We show that CO oxidation over Au/TiO₂ might proceed via a two site mechanism with oxygen adsorbing and dissociating at the Au/oxide interface or the perimeter of Au particles and CO adsorbing on Au sites away from the interface. The electronic fingerprint of active Au is a function of external conditions, and it is likely that most Au atoms are populated by CO and electronically neutral. Under highly oxidizing conditions, the Au/oxide interface can accommodate oxygen adsorbates, and these Au atoms will have a cationic fingerprint due to their interaction with oxygen. The choice of precursors used to synthesize catalysts as well as the catalyst preparation and pretreatment procedures significantly affect the electronic characteristics and catalytic activity of Au nano-structures. Based on our first-principles analysis we propose a hypothesis that might help us understand these experimental observations.