Significant progress has been made over the last decade in elucidating the mechanisms employed by receptor protein tyrosine kinases (RTKs) in transducing extracellular signals critical for the regulation of diverse cellular activities. Nevertheless, revealing the biological significance of a subset of the RTKs that contain catalytically inactive protein tyrosine kinase domains has proven more elusive. ErbB3 has served as the prototype for models of catalytically inactive RTK function, performing the role of signal diversification in heterodimeric receptor complexes with other ErbB subfamily members. The receptor related to tyrosine kinases (RYK) is unique amongst the catalytically inactive RTKs. Based on structural or functional properties of the extracellular domain, RYK cannot be classified into an existing RTK subfamily. Recent genetic analyses of mouse Ryk and its Drosophila orthologue derailed have defined a role for this novel subfamily of receptors in the control of craniofacial development and neuronal pathway selection, respectively. Recent biochemical data lead us to propose a model that involves RYK in signal crosstalk and scaffold assembly with Eph receptors. This model is consistent with the established roles of Eph receptors and ephrins in craniofacial and nervous system morphogenesis. BioEssays 23:34-45, 2001.