Multiple sclerosis treatment has been transformed by the successful development of immunotherapies, which efficiently reduce disease activity and related clinical relapses during the relapsing-remitting phase of the disease. However, preventing accumulation of disability progression, the consequence of axonal and neuronal damage and loss, remains a major unmet need and a therapeutic challenge in particular during the progressive phase of the disease. One strategy to counteract neurodegeneration is to promote neuroprotection by enhancing myelin regeneration, hence restoring nerve conduction and metabolic support to the axon. Preclinical research has provided targets to improve brain and spinal cord remyelination paving the way for translation to humans. From these initial promising forays, further problems have emerged, including how to best design these clinical trials, and appropriately measure outcomes. These need further work to translate efficacious pro-remyelination therapies to people with multiple sclerosis, but there is real hope now that we are on our way to success.