Artificial photosynthesis is envisioned as a promising strategy to convert sunlight, a practically unlimited and sustainable source of energy, into chemical fuels. In this scheme, the oxidation of water molecules is necessary to provide the electrons than will be employed in the synthesis of chemical fuels. Water oxidation is a particularly challenging reaction because it is a thermodynamically uphill multielectronic process with large activation barriers, but it is key for the realization of artificial photosynthesis because water is the only earth abundant molecule that can provide electrons in a massive and sustainable manner. Therefore, catalysts are needed for eluding the large intrinsic kinetic barriers of the reaction. In nature, water oxidation is catalyzed by a Mn tetrameric species, which enables O–O formation under the inherent mild physiological conditions trough a putative high valent manganese oxo species. Taking natural water oxidation as model, molecular catalysts operating under homogeneous conditions have been explored with the objective of providing basic understanding at molecular scale of the factors that govern this reaction, which eventually will receive utility in the design of efficient water oxidation devices. Traditionally, water oxidation has been studied with ruthenium and manganese based systems, but more recently attention has been shifted toward catalysts based on iridium and first row transition metals: the former due to their extraordinary performance and the latter because of their favorable cost, availability and environmental impact when compared with second and third row transition metals. The topic has been very actively explored and important lessons have been gained. Catalysts based on first row transition metals poise specific problems in terms of stability because generally their metal-ligand bonds are labile and because reaching their high oxidation states require high oxidation potentials. Consequently, high valent states of these metals are exceedingly reactive, readily prone to engage in oxidative decompositionpaths. Catalyst design is crucial for circumventing these problems and has enabled the discovery of extraordinarily reactive yet reasonably stable catalysts, comparable to the best examples based on second and third row transition metals. The following chapter reviews key contributions to the field. The manuscript does not intend to be comprehensive, but instead, selected and in our opinion representative examples are discussed.