The effects of oxygen concentration and ambient pressure on fuel cell performance are explored both in theory and in experiment. For fuel cells in general the effect due to a change in oxygen concentration is shown to be fundamentally different than the effect due to a change in cathode pressure, even if partial pressure is held constant. For a proton exchange membrane fuel cell, a significant reason for this difference comes from the nature of mass diffusion processes in the fuel cell structure, which infers that there is an optimum fuel cell design (macroscale and microscale) for a given operating pressure and oxygen concentration. In the experimental work a proton exchange membrane fuel cell was subjected to varying atmospheric conditions from sea level to 53,500 ft (16,307 m) with results analyzed up to 35,000 ft (10,668 m). The results showed that at low current density operation a decrease in either cathode pressure or concentration led to an increase in irreversible losses associated with reaction kinetics (activation polarization) and confirmed the differing effects of cathode pressure and oxygen concentration. Consideration of all these effects enables both fuel cell-and system-level optimization of aeronautical fuel cell-based power systems.