Multiple sclerosis (MS) is characterized by multifocal areas within the CNS of demyelination with relative but not absolute axonal sparing. Initial lesion development appears dependent on T cell infiltration into the CNS; however, lesion expansion may reflect tissue injury induced by additional effector mechanisms derived from cells of the immune system and endogenous CNS cells (glial cells). This relative susceptibility to injury in MS of myelin and its cell of origin, the oligodendrocyte (OL), could reflect either the properties of the effectors or the targets. Effector-determined susceptibility could relate to presence of OL/myelin-restricted T cells or antibody. OLs, at least in vitro, express MHC class I molecules and are susceptible to CD8(+)T cell-mediated cytotoxicity. OL/myelin-specific antibodies are identified in MS lesions and could induce injury via complement- or ADCC-dependent mechanisms. OLs are susceptible to injury-mediated by non-specific cell effectors including NK cells, NK-like T cells (CD56(+)), and gamma/delta T cells via perforin/granzyme-dependent mechanisms. In vitro studies of OL injury mediated via tumor necrosis factor (TNF) and CD95 indicate that differential glial cell susceptibility to injury can depend on cell surface receptor expression and intracellular signaling pathways that are activated. These target-determined susceptibility factors may be amenable to neuroprotective therapies.