Cytochrome c oxidase (COX) is the terminal oxidase of the mitochondrial respiratory system. This enzyme reduces molecular oxygen (O(2)) to water in a reaction coupled with the pumping of protons across the mitochondrial inner membrane. Progress in investigating the reaction mechanism of this enzyme has been limited by the resolution of its X-ray structure. Bovine heart COX has provided the highest resolution (1.8 Å) X-ray structure presently available among the terminal oxidases. The reaction mechanism of the bovine heart enzyme has been the most extensively studied, particularly with respect to (1) the reduction of O(2) to water without release of reactive oxygen species, (2) the mechanism of coupling between the O(2) reduction process and proton pumping, (3) the structural basis for unidirectional proton transfer (proton pumping), and (4) the effective prevention of proton leakage from the proton-pumping pathway to the proton pathway used for generation of water molecules. In this chapter, we will review recent structural studies of bovine heart COX and discuss the mechanisms described earlier in context of the structural data.