Water electrolysis coupled to renewable energy sources has become in a crucial technique for the green hydrogen production. Hydrogen economy is currently in the spotlight to solve energy demands due to its advantages such as clean, sustainable, low footprint, as well as high-power density which is 3 times above gasoline and diesel. To produce large quantities of hydrogen, proton exchange membrane water electrolysis (PEMWE) has arisen as a promising system to solve hydrogen demands. The heart of the PEMWE consists in a membrane electrode assembly (MEA), where two gas diffusion layers (GDLs), hosting the respective catalysts, are sandwiched between an ionomer membrane. Commonly, noble metals are needed as catalyst in the anode (Ir, Ru) and cathode (Pt) to reach high current densities maintaining low cell voltages. The large content of noble metals, their high cost, and accelerated corrosion rates at high cell voltages are some drawbacks that limit the industrialization and commercialization of PEMWE technology. Replacing, decreasing, or simply extending the operational lifetime of these noble metals have a positive impact on the hydrogen economy. Molybdenum is an earth-abundant metal with low-cost which has been already used to produce highly active electrocatalysts, that can potentially replace Pt. However, most electrocatalytic studies are restricted to three-electrode cells with different operational conditions than those employed in PEM cells. The latter makes a complicated task to predict the performance of the catalyst and stability under relevant instrial applications. Here, we investigated the viability of using three selected Mo-based nanomaterials (1T’-MoS2, Co-MoS2, and ß-Mo2C) as potential electrocatalysts to replace Pt in PEMWE systems. We investigated the effects of replacing Pt in the catalyst loading, charge transfer resistance, kinetics, operational stability, and hydrogen production efficiency during PEMWE operation. Furthermore, we developed a methodology to identify the effects of tuning the cathode catalyst while keeping the anode catalyst in the overall kinetics of PEMWE system. Our results point that electrochemical performance in traditional open cell might not strictly predict the performance that could be seen in PEMWE cells due to differences in interfaces, contact between the components and porosity of the macroscopic catalyst layers. Among the catalyst studied, 1T’-MoS2 exhibited low overpotential associated to low charge transfer resistance while reaching 1 A cm-2 at 1.9 V. Our study highlights the importance to continue developing efficient electrocatalysts to replace noble metals suitable for PEMWE systems. Figure 1