Multiple sclerosis (MS) has neurodegenerative features including neuronal and axonal loss in demyelination lesions and widespread atrophy of the brain. The cause of this neurodegeneration has been largely attributed to inflammation but other mechanisms, including those associated with classic neurodegenerative disease, might also be involved in the MS pathogenesis. Certain noninvasive tests such as magnetization transfer imaging, diffusion weighted imaging and proton magnetic resonance spectroscopy might be superior in early detection of axonal loss. In the current review, the authors discuss the current understanding of the neurodegenerative mechanisms in MS, agents with neuroprotective properties and their possible application in the treatment of MS.