Electrocatalytic water splitting driven by renewable energy input to produce clean H2 has been widely viewed as a promising strategy of the future energy portfolio. Currently, the state-of-the-art electrocatalysts for water splitting in acidic solutions are IrO2 or RuO2 for the O2 evolution reaction (OER) and Pt for the H2 evolution reaction (HER). Realization of large-scale H2 production from water splitting requires competent nonprecious electrocatalysts. Despite the advances of decades in this field, several challenges still exist and need to be overcome: (1) Most efforts in the design of nonprecious electrocatalysts have focused on developing HER catalysts for acidic conditions but OER catalysts for alkaline conditions owing to their thermodynamic convenience, potentially resulting in incompatible integration of the two types of catalysts and thus inferior overall performance. (2) In conventional water electrolysis, HER and OER are strictly coupled and therefore H2 and O2 are produced simultaneously, which may lead to explosive H2/O2 mixing due to gas crossover. Meanwhile, the coexistence of H2, O2, and electrocatalysts could produce reactive oxygen species that might shorten the lifetime of an electrolyzer. (3) The HER rate is often limited by that of OER due to the more sluggish kinetics of the latter, which lowers the overall energy conversion efficiency. Moreover, the product of OER, O2, is not highly valuable. (4) It remains challenging to develop efficient and low-cost H2 storage and transport systems for the future H2 economy. In this Account, we describe recent progress in innovative strategies to address the aforementioned four challenges in conventional water electrolysis. These novel strategies include (1) overall water electrolysis based on bifunctional nonprecious electrocatalysts (or precursors) to drive both HER and OER under the same conditions, (2) decoupled water electrolysis achieved by redox mediators for temporally and spatially separating HER from OER, (3) hybrid water electrolysis by integrating thermodynamically more favorable organic upgrading reactions to replace OER, and (4) tandem water electrolysis by utilizing biocatalysts for converting the in situ produced H2 with foreign compounds (e.g., CO2 and N2) to more valuable products. Finally, the remaining challenges and future perspectives are also presented. We hope this Account will function as a momentum call for more endeavors into the development of advanced electrocatalytic systems and novel strategies for practicable H2 production from water as well as the electrocatalytic upgrading of diverse organic compounds.