We report the genomic organization of the mouse orphan receptor related to tyrosine kinases (Ryk), a structurally unclassified member of the growth factor receptor family. The mouse RYK protein is encoded by 15 exons distributed over a minimum of 81 kilobases. Genomic DNA sequences encoding a variant protein tyrosine kinase ATP-binding motif characteristic of RYK are unexpectedly found in two separate exons. A feature of the gene is an unmethylated CpG island spanning exon 1 and flanking sequences, including a TATA box-containing putative promoter and single transcription start site. Immunohistochemical examination of RYK protein distribution revealed widespread but developmentally regulated expression, which was spatially restricted within particular adult organs. Quantitative reduction of Southern blotting stringency for the detection of Ryk-related sequences provided evidence for a retroprocessed mouse pseudogene and a more distantly related gene paralogue. Extensive cross-species reactivity of a mouse Ryk kinase subdomain probe and the cloning of a Ryk orthologue from Caenorhabditis elegans demonstrate that Ryk and its relatives encode widely conserved members of a novel receptor tyrosine kinase subfamily.