Life machinery, although overwhelmingly complex, is rooted on a rather limited number of molecular processes. One of the most important is protein-protein interaction. Metabolic regulation, protein folding control, and cellular motility are examples of processes based on the fine-tuned interaction of several protein partners. The region on the protein surface devoted to the recognition of a specific partner is essential for the function of the protein and is, therefore, likely to be conserved during evolution. On the other hand, the physical chemistry of amino acids underlies the mechanism of interactions. Both evolutionary and energetic constraints can then be used to build scoring functions capable of recognizing interaction sites. Our working hypothesis is that residues within the interaction interface tend at the same time to be evolutionarily conserved (to preserve their function) and to provide little contribution to the internal stabilization of the structure of their cognate protein, to facilitate conformational adaptation to the partner. Here, we show that for some classes of protein partners (for example, those involved in signal transduction and in enzymes) evolutionary constraints play the key role in defining the interaction surface. In contrast, energetic constraints emerge as more important in protein partners involved in immune response, in inhibitor proteins, and in structural proteins. Our results indicate that a general-purpose scoring function for protein-protein interaction should not be agnostic of the biological function of the partners.