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 multi-domain 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.