The results of molecular cloning and homology searches have identified a minimum of five different proteins of the endothelial differentiation gene (edg) encoded subfamily of GPCRs. Edg protein GPCRs show amino acid sequence identity of 31% to 34% as a subfamily, but contain two homology clusters with greater similarity of structures and functions. One cluster of high amino acid sequence homology includes Edg-2 and Edg-4 proteins, that encode GPCRs for LPA, but not lysosphingolipids. A second homology cluster encompasses Edg-1, Edg-3 and Edg-5. Edg-3 and Edg-5 encode GPCRs specific for S1P, but not LPA. Preliminary data suggest that Edg-1 encodes a GPCR for S1P and one or more other lysosphingolipids, but the signals evoked by S1P alone are far weaker than those transduced by Edg-3 and Edg-5. Similarities of the structures of genes for the respective homology clusters supports this tentative classification of the Edg protein GPCRs. Future research will be directed to completion of the elucidation of genomic organization and signaling pathways, and a greater understanding of the breadth of functional roles of Edg proteins in development and activities of the nervous, cardiovascular, endocrine and immune systems.