The proteolipid proteins (PLP and DM-20) of the mammalian central nervous system are the major integral membrane proteins of the myelin sheath. These proteins have four hydrophobic domains that are embedded in the bilayer (Popot et al. , 1991; Weimbs and Stoffel 1992). They are not glycosylated, and they function in adhesive interactions that generate the intraperiod line. The finding that only a very few variations in PLP/DM-20 sequence are normally tolerated, taken together with the knowledge that many single amino acid substitutions yield dysmyelinating phenotypes, has led to the notion that in order to function correctly in myelination, the mammalian PLP/DM-20 have remained essentially invariant throughout evolution. This notion was challenged by immunocytochemical (see Waehneldt, 1990 for review) and new molecular biological findings (Kitagawa et al. , 1993; Yan et al. , 1993) which showed that in cartilaginous fish (Kitagawa et al. , 1993) and mouse (Yan et al. , 1993), proteolipid-like proteins whose sequences were quite divergent from the mammalian PLP/DM-20 could be detected. These findings led to the inescapable conclusion that the proteolipid family originated quite early in vertbrate evolution- at least 400 million year before present (400 MYR BP)