Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that is pathologically characterized by inflammatory demyelination and neuro-degeneration. Axonal damage, along with neuronal loss, occurs from disease onset and may lead to progressive and permanent disability. In contrast with the inflammatory pathways, the molecular mechanisms leading to MS neurodegeneration remain largely elusive. With improved understanding of these mechanisms, new potential therapeutic targets for neuroprotection have emerged. We review the current understanding of neurodegenerative processes at play in MS and discuss potential outcome measures and targets for neuroprotection trials.