There is an abundance of data on protein interactions and protein complexes, both from conventional smallscale experiments collected over the decades, including threedimensional structures, and more recently by largescale functional genomics experiments. We can now draw on the information available about protein interactions in order to study the evolution of interactions. We have shown that interactions, just like individual proteins, frequently emerge by duplication and divergence. The duplication of a protein that engages in proteinprotein interactions raises issues about the stoichiometry and equilibrium of protein complexes when the quantity of one component increases. Nevertheless, our results indicate that most interactions and complexes have evolved by stepwise duplications of individual proteins engaged in interactions. We show that duplicated complexes retain the same overall function, but have different binding specificities and regulation, revealing that duplication is associated with functional specialization[1,2]. From analysis of crystal structures of proteins as well as the domain architectures of multidomain proteins, it is clear that physical interactions between identical or homologous domainsand protein chains are extremely common [3,4]. How have this particular class of interactions evolved, and