The TGF-beta superfamily exhibits a feature making it distinct from many other growth factor families in that the inadequate number of ligands and receptors premises a high degree of promiscuity in ligand-receptor interaction. This highlights the importance of even small differences in affinities and specificities between different binding partners to maintain the broad spectrum of their well defined biological functions. Despite the promiscuous interactions recent data reveal differences in receptor recruitment, architectures of these assemblies and specific modulation by a multitude of extracellular as well as membrane-associated factors. These modulatory mechanisms might possibly add specificity towards defined biological functions despite the overlapping usage of receptors by various ligands.