Here we briefly review our understanding of the immune response to myelin-derived glycolipids during an inflammatory autoimmune response in the central nervous system (CNS). We focus primarily on the recognition of the self-glycolipid sulfatide by a distinct population of non-invariant NK T cells. The results of studies we have obtained so far in investigating the presentation of sulfatide by CNS-resident cells including microglia and their interactions with T cells indicate that this pathway might be successfully targeted for the treatment of autoimmune demyelination in multiple sclerosis.