Summary: Water electrolysis powered by renewables provides a green approach to hydrogen production to support the “hydrogen economy.” However, the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) are tightly coupled in both time and space in traditional water electrolysis, which brings inherent operational challenges, such as the mixture of H2/O2 and the limited HER rate caused by the sluggish kinetics of OER. Against this background, decoupling H2 and O2 production in water electrolysis by using the auxiliary redox mediator was first proposed in 2013, in which O2 and H2 are produced at different times, rates, and/or locations. The decoupling strategy offers not only a new way to facilitate renewables to H2, but it can also be applied in other chemical or electrochemical processes. This review describes recent efforts to develop high-performance redox mediators, optimized strategies in decoupled water electrolysis, the design of electrolyzer configuration, the challenges faced, and the prospective directions.