Fuel cells are a viable alternative to mankind’s dependence on fossil fuels. Unfortunately, fuel cells are not yet on the market, mostly because of the lack of efficient and affordable catalysts for the sluggish chemical reactions driving cells’ operation, such as the oxygen reduction reaction (ORR). Indeed, several families of ORR catalysts, for the most part metallic alloy nanoparticles (NPs), have proven excellent in terms of both activity and stability when tested in standard three-electrode cells, i.e. ex situ. When used inside operating fuel cells though, the very promising nanoalloy catalysts produced so far are often found less efficient than expected. The reason is that the nanoalloy particles would undergo specific atomic-level changes that inflict significant losses in their ORR activity, thereby limiting the cells’ performance. Despite extensive research, the driving force, scope and dynamics of atomic-level changes of functioning nanoalloy catalysts remain not well understood and so the resulting losses in their ORR activity remain difficult to limit. We will present results from combined energy dispersive x-ray spectroscopy (EDS) and total high-energy x-ray scattering studies of nanosized metallic NPs from Pd-Sn and Pt-Ni-Cu families as they function at the cathode of an operating proton exchange membrane fuel cell (PEMFC). We will show that the technique allows characterizing ORR catalysts inside PEMFCs with atomic-level precision (~ 0.02 Å) and element specificity (~ 2-3 at. %) in both time (~1 min) and space (~µm) resolved manner. In particular, it provides unique information for the chemical composition, geometric surface area, phase content, 3D structure and strength of interactions between the constituent atoms of studied nanocatalysts. We will also show how the new experimental knowledge obtained provides a firm structural basis for synthesizing improved catalysts for ORR inside PEMFCs.