Understanding the structure–activity relationship (SAR) is essential for catalyst innovation. Here we report a methodology to unravel the elusive SAR of fuel-cell catalysts by individually studying the electronic structure–surface reactivity (ES–SR) relationship and the surface reactivity–catalytic activity (SR–CA) relationship. In the light of this methodology, we demonstrate a strategy for optimizing fuel-cell alloy catalysts, featuring the rational manipulation of the surface reactivity through electronic effects. For Pt-alloy cathode catalysts with Pt-rich surface, such as Pt-segregated Pt-Ni alloy, the key is to weaken the surface reactivity through the strain effect; optimum catalytic activity toward the oxygen reduction reaction (ORR) is predicted to be achieved on a contraction in Pt lattice by 1.9%. For Pd-based anode catalysts, on the other hand, the ligand effect will play an important role, and enhancing the surface reactivity by alloying with Cu can boost the catalytic activity toward the formic-acid oxidation reaction (FAOR) by orders in magnitude.