Remyelination in multiple sclerosis is in most cases insufficient, leading to irreversible disability. Different and nonexclusive factors account for this repair deficit. Local inhibitors of the differentiation of oligodendrocyte progenitor cells (OPCs) might play a role, as well as axonal factors impairing the wrapping process. Alternatively, a defect in the recruitment of OPCs toward the demyelinated area may be involved in lesions with oligodendroglial depopulation. Deciphering the mechanisms underlying myelin repair success or failure should open new avenues for designing strategies aimed at favoring endogenous remyelination.