The metal-oxo M4O4 "cubane" topology is of special significance to the field of water oxidation as it represents the merging of bioinspired structural principles derived from natural photosynthesis with successful artificial catalysts known to date. Herein, we directly compare the rates of water oxidation/O-2 evolution catalyzed by six cobalt-oxo clusters including the Co4O4 cubanes, Co4O4(OAc)(4)(py)(4) and [Co4O4(OAc)(2)(bpy)(4)](2+), using the common Ru(bpy)(3)(2+)/S2O82- photo-oxidant assay. At pH 8, the first-order rate constants for these cubanes differ by 2-fold, 0.030 and 0.015 s(-1), respectively, reflecting the number of labile carboxylate sites that allow substrate water binding in a pre-equilibrium step before O-2 release. Kinetic results reveal a deprotonation step occurs on this pathway and that two electrons are removed before O-2 evolution occurs. The Co4O4 cubane core is shown to be the smallest catalytic unit for the intramolecular water oxidation pathway, as neither "incomplete cubane" trimers [Co3O(OH)(3)(OAc)(2)(bpy)(3)](2+) and [Co3O(OH)(2)(OAc)(3)(py)(5)](2+) nor "half cubane" dimers [Co-2(OH)(2)(OAc)(3)(bpy)(2)](+) and [Co-2(OH)(2)(OAc)(3)(py)(4)](+) were found capable of evolving O-2, despite having the same ligand sets as their cubane counterparts. Electrochemical studies reveal that oxidation of both cubanes to formally Co-4(3III,IV) (0.7 V vs Ag/AgCl) occurs readily, while neither dimers nor trimers are oxidized below 1.5 V, pointing to appreciably greater charge delocalization in the [Co4O4](5+) core. The origin of catalytic activity by Co4O4 cubanes illustrates three key features for water oxidation: (1) four one-electron redox metals, (2) efficient charge delocalization of the first oxidation step across the Co4O4 cluster, allowing for stabilization of higher oxidizing equivalents, and (3) terminal coordination site for substrate aquo/oxo formation.