The elucidation of governing principles of catalyst activity from fundamental research on well-defined model systems, combined with the advances in controlled synthesis of the transition metal nanocatalysts, have led to the rational design and development of advanced nanocatalysts. One principle is to tune surface strain and thereby modulate the surface electronic structure and catalytic reactivity. This approach has been employed to identify transition metal and (hydroxy)oxide catalysts for energy-relevant electrocatalytic reactions. For oxygen reduction reaction on platinum as an example, previous studies have indicated that a 1% compressive strain may improve the activity over 300%. While strain tuning of catalysts is very promising for activity enhancement, two challenges continue to limit the performance of these materials. First, the effect of strain on high-surface-area nanoparticle catalysts is often convoluted with nanoparticle shape and by the presence of undercoordinated defects, while model catalysts, where high specific activities is achievable by strain tuning, have prohibitively small mass activities and are therefore of limited practical interest. Thus, there is an urgent need to develop strain tuning strategies for nanomaterials that preserve the structural simplicity and high specific activity of single crystals while simultaneously possessing high surface areas and mass activities. In addition, strain in catalyst overlayers is often imposed by heterosubstrates, which may lead to interfacial reconstructions and strain release. In this talk, in combination DFT calculations, electrochemical tests and TEM characterization, we will present a strategy to resolve these problems through self-driven strain tuning in transition metal nanocrystals with the characteristics of low-index single-crystal surfaces. As we demonstrate for the oxygen reduction reaction in alkaline fuel cells, this relationship could be exploited to enhance reaction rates by orders of magnitude in comparison with nanoparticle catalysts, suggesting that this self-driven tuning mechanism in transition metal nanocrystals can be a powerful strategy for the design and development of advanced catalytic materials.