The water oxidation reaction in nature is carried out by Photosystem II (PS II), a multi subunit membrane protein complex. This light-driven reaction is made possible by a spatially separated, yet temporally connected series of cofactors along the electron transfer chain of PS II over 40 Å, through the donor (the Mn4CaO5 catalytic center), the reaction center chlorophylls, to the mobile quinone electron acceptors. Such chemical architecture provides an ideal platform to investigate how to control multi-electron/proton chemistry, using the flexibility of metal redox states, in coordination with the protein and the water network. Understanding insights of nature’s design gives inspiration of how to build artificial photosynthetic devices, where the controlled accumulation of charge and high selectivity of products is currently challenging. To solve the mechanism of the water oxidation reaction in PS II, our strategy has been to follow the structural and chemical sequence of all events in the enzyme that lead to O-O bond formation, and to understand the cycle of the catalytic reaction at the atomic and electronic structure level.1-3 We have developed and applied new methods in crystallography and X-ray spectroscopy at the X-ray free electron lasers (XFELs). We will discuss the interplay of structural and chemical changes of PS II through the catalytic cycle.