A substantial fraction of protein interactions in the cell is mediated by families of protein modules binding to relatively short linear peptides. Many of these interactions have a high dissociation constant and are therefore suitable for supporting the formation of dynamic complexes that are assembled and disassembled during signal transduction. Extensive work in the past decade has shown that, although member domains within a family have some degree of intrinsic peptide recognition specificity, the derived interaction networks display substantial promiscuity. We review here recent advances in the methods for deriving the portion of the protein network mediated by these domain families and discuss how specific biological outputs could emerge in vivo despite the observed promiscuity in peptide recognition in vitro.