<jats:title>Abstract</jats:title><jats:p>Water oxidation (WO) is a central reaction in the photo‐ and electro‐synthesis of fuels. Iridium complexes have been successfully exploited as water oxidation catalysts (WOCs) with remarkable performances. Herein, we report a systematic study aimed at benchmarking well‐known Ir WOCs, when NaIO<jats:sub>4</jats:sub> is used to drive the reaction. In particular, the following complexes were studied: <jats:italic>cis</jats:italic>‐[Ir(ppy)<jats:sub>2</jats:sub>(H<jats:sub>2</jats:sub>O)<jats:sub>2</jats:sub>]OTf (ppy=2‐phenylpyridine) (<jats:bold>1</jats:bold>), [Cp*Ir(H<jats:sub>2</jats:sub>O)<jats:sub>3</jats:sub>]NO<jats:sub>3</jats:sub> (Cp*=1,2,3,4,5‐pentamethyl‐cyclopentadienyl anion) (<jats:bold>2</jats:bold>), [Cp*Ir(bzpy)Cl] (bzpy=2‐benzoylpyridine) (<jats:bold>3</jats:bold>), [Cp*IrCl<jats:sub>2</jats:sub>(Me<jats:sub>2</jats:sub>‐NHC)] (NHC=N‐heterocyclic carbene) (<jats:bold>4</jats:bold>), [Cp*Ir(pyalk)Cl] (pyalk=2‐pyridine‐isopropanoate) (<jats:bold>5</jats:bold>), [Cp*Ir(pic)NO<jats:sub>3</jats:sub>] (pic=2‐pyridine‐carboxylate) (<jats:bold>6</jats:bold>), [Cp*Ir{(P(O)(OH)<jats:sub>2</jats:sub>}<jats:sub>3</jats:sub>]Na (<jats:bold>7</jats:bold>), and <jats:italic>mer</jats:italic>‐[IrCl<jats:sub>3</jats:sub>(pic)(HOMe)]K (<jats:bold>8</jats:bold>). Their reactivity was compared with that of IrCl<jats:sub>3</jats:sub>⋅<jats:italic>n</jats:italic> H<jats:sub>2</jats:sub>O (<jats:bold>9</jats:bold>) and [Ir(OH)<jats:sub>6</jats:sub>]<jats:sup>2−</jats:sup> (<jats:bold>10</jats:bold>). Most measurements were performed in phosphate buffer (0.2 <jats:sc>m</jats:sc>), in which <jats:bold>2</jats:bold>, <jats:bold>4</jats:bold>, <jats:bold>5</jats:bold>, <jats:bold>6</jats:bold>, <jats:bold>7</jats:bold>, and <jats:bold>10</jats:bold> showed very high activity (yield close to 100 %, turnover frequency up to 554 min<jats:sup>−1</jats:sup> with <jats:bold>10</jats:bold>, the highest ever observed for a WO‐driven by NaIO<jats:sub>4</jats:sub>). The found order of activity is: <jats:bold>10</jats:bold>><jats:bold>2</jats:bold>≈<jats:bold>4</jats:bold>><jats:bold>6</jats:bold>><jats:bold>5</jats:bold>><jats:bold>7</jats:bold>><jats:bold>1</jats:bold>><jats:bold>9</jats:bold>><jats:bold>3</jats:bold>><jats:bold>8</jats:bold>. Clues concerning the molecular nature of the active species were obtained, whereas its exact nature remains doubtfully.</jats:p>