Receptor tyrosine kinases play key roles in signal transduction across cell surfaces in biological systems, including the vascular system. These receptors comprise a large and diverse family of catalytically related proteins that, on the basis of sequence and structural similarities, can be divided into several different evolutionary subfamilies. The cloning and characterization of Tie-1 (also designated Tie), a novel human endothelial cell surface receptor tyrosine kinase, has been reported. The extracellular domain of the predicted Tie-1 protein product has an unusual multidomain structure consisting of a cluster of three epidermal growth factor homology motifs localized between two immunoglobulin-like loops, which are followed by three fibronectin type III repeats next to the transmembrane region. An additional member of this family has been identified as Tie-2 (also designated Tek). Tie-1 and Tie-2 have been shown to be encoded by distinct genes and to represent members of a new class of receptor tyrosine kinases.