In the vertebrate peripheral nervous system, Schwann cells form the myelin sheath, the multilayered membrane that insulates axons and allows the rapid propagation of electrical signals. Now, on p. 2673, William Talbot and colleagues report that, as in zebrafish, the orphan G-protein-coupled receptor Gpr126 is essential for myelination and other aspects of peripheral nerve development in mammals. The researchers show that a mutation in Gpr126 causes a severe congenital hypomyelinating peripheral neuropathy in mice and reduces the expression of differentiated Schwann cell markers. In addition, Gpr126 mutant mice lack Remak bundles (the non-myelinating Schwann cells associated with small calibre axons), and exhibit delayed sorting of large calibre axons by Schwann cells, suggesting that the Schwann cells are arrested at the promyelinating stage. Finally, they report, Gpr126 mutant mice develop abnormalities in the perineurium (the connective tissue that surrounds each nerve fibre bundle). Given these results, the researchers suggest that Gpr126 might represent a target for the treatment of demyelinating diseases of nerves.