The growth and chemical activity of Re, Pt, and Pt–Re bimetallic clusters supported on TiO2(110) have been studied. Pure Re clusters interact strongly with the titania support, resulting in the reduction of the titania surface, and the Re clusters also appear to be partially covered by TiO x at Re coverages as high as 13 ML. Bimetallic clusters can be grown from sequential deposition of Pt and Re in either order at high metal coverages (3.7 ML), where the number of initial nucleation sites is large; in contrast, at lower coverages (0.24 ML), pure Re clusters coexist with Pt–Re clusters for Re deposited on Pt due to the higher nucleation density of Re compared with Pt. The surface composition of the high coverage Pt on Re clusters is ∼100% Pt, but the Re on Pt clusters contain both Pt and Re at the surface after diffusion of some fraction of Re atoms in the bulk. The lower surface free energy of Pt compared to Re makes it thermodynamically favorable for Pt to remain at the surface when Pt is deposited on Re, whereas Re atoms deposited on the Pt clusters will diffuse into the clusters. Isotopic labeling experiments that incorporate 18O into the titania lattice demonstrate that lattice oxygen participates in both CO oxidation on the Pt on Re bimetallic clusters and recombination of carbon and oxygen to form CO on the Re-containing clusters.