The photosynthetic oxygen evolving complex (PSII-OEC) and the mitochondrial cytochrome c oxidase (CcO) not only catalyze anti-parallel reactions (the OEC oxidizes water to dioxygen, whereas CcO reduces dioxygen to water), they also share a number of uncanny molecular and mechanistic similarities. Both feature a redox-active polymetallic cluster that includes a key tyrosine, and both utilize a two-phase mechanism. In one phase the polymetallic cluster undergoes four sequential one-electron transfers: In the PSII-OEC, four successive photooxidations of the photosystem II reaction center P680 (to P680(+)) allows acceptance of 4 × 1e- from the Mn(4)Ca cluster; in CcO, four reduced cytochrome c Fe(2+) cations donate 4 × 1e- to the bimetallic center. In the second phase for each enzyme, the polymetallic cluster undergoes a single four-electron transfer with the O(2)/2 H(2)O redox couple. Intriguing mechanistic similarities between these two complex redox enzymes first delineated over a decade ago by Hoganson/Proshlyakov/Babcock et al. are updated and expanded in this article.