The current landscape of therapeutics designed to treat multiple sclerosis (MS) and its pathological sequelae is saturated with drugs that modify disease course and limit relapse rates. While these small molecules and biologicals are producing profound benefits to patients with reductions in annualized relapse rates, the repair or reversal of demyelinated lesions with or without axonal damage, remains the principle unmet need for progressive forms of the disease. Targeting the extracellular pathological milieu and the signaling mechanisms that drive neurodegeneration are potential means to achieve neuroprotection and/or repair in the central nervous system of progressive MS patients. The Nogo-A receptor-dependent signaling mechanism has raised considerable interest in neurological disease paradigms since it can promulgate axonal transport deficits, further demyelination, and extant axonal dystrophy, thereby limiting remyelination. If specific therapeutic regimes could be devised to directly clear the Nogo-A-enriched myelin debris in an expedited manner, it may provide the necessary CNS environment for neurorepair to become a clinical reality. The current review outlines novel means to achieve neurorepair with biologicals that may be directed to sites of active demyelination.