The Net Zero Emission scenario proposed by the International Energy Agency projects a required electrolytic generation of hydrogen equivalent to 3600 GW by 2050 [1], averaging to an annual installation of ~130 GW/a between 2023 and 2050. If this were to be provided by proton exchange membrane based water electrolyzers (PEM-WEs) based on platinum catalysts for the hydrogen evolution reaction (HER) and iridium catalysts for the oxygen evolution reaction (OER), the current PEM-WE noble metal requirements of ~0.7 gIr/kW and ~0.3 gPt/kW [1] would have to be drastically reduced in view of the noble metal supply constraints. As argued previously, for PEM-WEs to be sustainable on such a large scale would require to achieve platinum and iridium loadings of ~0.05 mg/cm2 electrode [2,3]. While the former can be easily achieved due to the fast HER kinetics on Pt, the latter requires either ultra-thin OER catalyst layers or improved OER catalysts with a substantially reduced iridium packing density (in units of gIr/cm3 electrode) [2], like the recently developed catalyst with a hydrous iridium oxide shell supported on a titanium oxide core (IrOx/TiO2) [4,5].In this contribution, we will discuss the effect of the design of membrane electrode assemblies (MEAs) and of the adjacent porous transport layers on PEM-WE performance. In general, the preparation of MEAs with low platinum loading cathodes is straightforward, due to the availability of carbon supported platinum catalysts (Pt/C) with a low Pt packing density. For the optimization of the ionomer content in the cathode electrode, however, its effect on the high current density performance and on the hydrogen permeation rate from cathode to anode have to be considered [6,7].With regards to the anode electrode, we will further discuss the MEA design challenges when targeting ultra-low iridium loadings. In the case of the ultra-thin catalyst layers that result when using conventional OER catalysts, additional contact resistances between the anode catalyst layer and the titanium based porous transport layer (Ti-PTL) are observed [2]. As will be shown, these can be largely mitigated by the use of a titanium based microporous layer (MPL) coated on the Ti-PTL, highlighting the importance of the interface between the PTL and the anode catalyst layer. In case of using the above described IrOx/TiO2 catalysts with low iridium packing density, their typically lower electrical conductivity also results in apparent contact resistances within and across the anode catalyst layer [4], which poses an additional constraint on the allowable range of the catalyst/ionomer ratio in the anode electrode. The interplay between the anode catalyst type, the anode ionomer content, and the type of interface between the anode electrode and the PTL (i.e., with and without MPL) will be discussed.