Using the binding energy of OH* and CO* on close-packed surfaces as reactivity descriptors, we screen bulk and surface alloy catalysts for methanol electro-oxidation activity. Using these two descriptors, we illustrate that a good methanol electro-oxidation catalyst must have three key properties: (1) the ability to activate methanol, (2) the ability to activate water, and (3) the ability to react off surface intermediates (such as CO* and OH*). Based on this analysis, an alloy catalyst made up of Cu and Pt should have a synergistic effect facilitating the activity towards methanol electro-oxidation. Using these two reactivity descriptors, a surface PtCu3 alloy is proposed to have the best catalytic properties of the Pt–Cu model catalysts tested, similar to those of a Pt–Ru bulk alloy. To validate the model, experiments on a Pt(111) surface modified with different amounts of Cu adatoms are performed. Adding Cu to a Pt(111) surface increases the methanol oxidation current by more than a factor of three, supporting our theoretical predictions for improved electrocatalysts.