To increase system efficiency and power density, the cathode air path of Polymer Electrolyte Membrane Fuel Cells (PEM FCs) is supercharged using electrically driven air bearing centrifugal compressors. To maximize system efficiency, the cathode air supply system must be designed to optimally fulfill the requirements of the PEM FC system while obeying the design constraints imposed by the electric compressor drive and the air bearing system. This article proposes a dedicated design process for PEM FC cathode air compressors. Using physically based component models, the impact of varying cathode stoichiometry and operating pressure on PEM FC system performance is assessed to derive the system efficiency optimal compressor operating strategy. The centrifugal compressor stage is subsequently designed to achieve optimum efficiency on this operating line using meanline performance models and three-dimensional computational fluid dynamics simulations. Novel test procedures and measurement equipment are employed to validate the compressor design. The design process is demonstrated using a PEM FC passenger car application as an example. It is shown that significant performance and efficiency gains are achievable when tailoring the cathode air supply system to the application at hand. In the given example, effective compressor efficiency is increased by Δηeff = 12%. Along with an optimized compressor operating strategy, an overall PEM FC system efficiency gain of Δηsys = 2.7% is achieved.