Proton exchange membrane fuel cells (PEMFCs) are attractive because of their high conversion efficiency, low pollution, lightweight, and high power density. A major area of challenges is the design and engineering of active, robust, and low-cost electrocatalysts. This report discusses recent findings of our investigations of the design and nano-engineering of platinum-vanadium-iron catalysts for use in PEMFC. The membrane electrode assembly was prepared using nano-engineered PtVFe nanoparticles with controlled composition and size supported on carbon as cathode electrocatalysts. The electrocatalytic activity and stability of the catalysts have been characterized by both rotating disk electrode and membrane electrode assembly measurements. The trimetallic catalysts have been shown to exhibit excellent electrocatalytic performance in PEMFC in comparison with commercial platinum catalysts. The results exhibited a good agreement between obtained these two types of measurements in terms of the dependence on particle size, composition, and thermal treatment condition. The catalysts also showed good stability, which are potentially useful for practical application in PEMFCs.