We present ultralow Ir-loaded (ULL) proton exchange membrane water electrolyzer (PEMWE) cells that can produce enough hydrogen to largely decarbonize the global natural gas, transportation, and electrical storage sectors by 2050, using only half of the annual global Ir production for PEMWE deployment. This represents a significant improvement in PEMWE's global potential, enabled by careful control of the anode catalyst layer (CL), including its mesostructure and catalyst dispersion. Using commercially relevant membranes (Nafion 117), cell materials, electrocatalysts, and fabrication techniques, we achieve at peak a 250× improvement in Ir mass activity over commercial PEMWEs. An optimal Ir loading of 0.011 mg_Ir cm^-2 operated at an Ir-specific power of ∼100 MW kg_Ir^-1 at a cell potential of ∼1.66 V versus RHE (85% higher heating value efficiency). We further evaluate the performance limitations within the ULL regime and offer new insights and guidance in CL design relevant to the broader energy conversion field.