The Ly-6 locus on mouse chromosome 15 encodes a family of 10-12 kDa proteins that are linked to the cell surface by a glycosylphosphatidyl-inositol anchor and have cell signaling and cell adhesion properties. Expression of Ly-6 proteins is tightly regulated during development; these proteins continue to serve as excellent differentiation surface markers on normal and abnormal cells, but their role in driving cellular differentiation is still emerging. Recent studies suggest that Ly-6 gene products participate in regulating signaling through other cell type-specific receptors, perhaps by virtue of these proteins being localized in lipid rafts that play a key role in relaying signals from the membrane to the nucleus. Ligands for some Ly-6 proteins have been reported; the consequence of their interactions with the Ly-6 receptor remains to be fully uncovered. Mouse Ly-6-like proteins have also been reported from a variety of life forms ranging from Caenorhabditis elegans to humans that show a limited amino acid identity and share structural features with members of mouse Ly-6. Despite these similarities, the non-murine Ly-6 proteins bind distinct ligands and appear to have different cellular functions. All members of the Ly-6 super gene family perhaps evolved from an ancestral gene by a gene duplication mechanism.