Multiple sclerosis (MS), a chronic demyelinating central nervous system (CNS) disorder, is the leading cause of acquired neurological disability in young adults. Current treatments are immunomodulatory and provide temporary relief during relapses, but mostly lack an effect on disability progression, caused by axonal degeneration. Remyelination (myelin repair) of demyelinated axons reduces axonal degeneration in mice and patients, but this process eventually fails with disease progression. Thus, promoting remyelination in MS is a potential therapeutic strategy to prevent irreversible neurological deficits. So far, the search for pro-remyelinating agents has focused primarily on compounds that promote differentiation of oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the CNS. Yet, clinical trials performed have shown modest functional benefits and scarce impact on the clinical outcome. In this talk, I will we argue that achieving clinical benefits in MS patients will likely require complementary/alternative approaches to stimulate remyelination . I will present our recently published data on gene therapy as a therapeutically relevant strategy for stimulating OPC repopulation of demyelinating lesions that, as I will show, fails in the disease. Lastly, I will briefly present our ongoing work that addresses the hypothesis that remyelination in MS fails due to metabolic deficit that prevents OPCs from synthesizing new myelin.