The studies of the oxygen reduction reaction on well-defined surfaces have guided the approach to design of the real world nanostructured catalysts. Insights from single crystalline systems and thin film surfaces have yielded atomically precise information about surface structure and alloying with other metals in the quest to improve their intrinsic catalytic activity. These experimental efforts are also producing information necessary for the design of catalysts with enhancing stability. These accomplishments were achieved through electrochemical in situ ICP-MS detection of parts per trillion levels of metal dissolution. Atomic level insight, has guided the chemical synthesis of well-defined nanoscale surfaces and creation of novel architectures that are associated with advanced catalytic performance. The progress in platinum-transition metal alloy nanocatalysts will be in focus of this lecture, with the goal of improving the activity and durability of the oxygen reduction electrocatalyst in a proton exchange membrane fuel cell. Atomic level control of the positioning of elements within alloy nanocrystals enables the design of shapes and surfaces that mimic the key descriptors discovered through research on well-defined surfaces. The meticulous characterization of nanocatalysts using extremely high-purity conditions and cutting-edge techniques provides greater understanding of their performance and degradation pathways. This knowledge allows better implementation of electrocatalysts in membrane electrode assemblies (MEA) for demonstration of expected performance in a fuel cell vehicle. An MEA is still viewed as a complex system with multiple interfaces. The catalyst, its support, water, ionomer, and gaseous reactants create challenging environment to control and engineer at the level that would be capable to address all technical targets that are necessary for wide deployment of this technology. The transition from high-purity liquid electrolytes into MEA still needs to be fully addressed in order to boost fuel cell stack performance. More recent research directions, such as platinum group metal (PGM) free catalysts will also be discussed. The main focus is being placed on replacement of platinum by more abundant cost effective constituents that could significantly lower the total cost of fuel cell. Typical PGM-free catalysts are consisted of transition metal sites coordinated by nitrogen dopants within a carbon matrix. While their intrinsic activity requires improvement, stability is equally critical in order to implement this class of materials in real fuel cells. Once again, well-defined, high-precision characterization and synthesis are proving vital to development of new generation of cathode catalysts. The overall research strategy presented here exhibits the merits of a continuous pipeline from fundamental to applied research in the development of fuel cell technology.