The direct electrochemical conversion of chemical energy in low-temperature fuel cells is underpinned by the activity of the catalytic center. The latter, in nanodivided form (either precious or non-precious), is also influenced by the effect of the support, which serves as electron conductor. Herein, we discuss the relevant physicochemical driving force that leads to a “strong interaction” with substrates of carbon and oxide nature. Due to the interest in the activity and stability, special attention is given to the cathodic process, that is, to the oxygen reduction reaction (ORR).