The damage of axons and neurons in multiple sclerosis (MS) is well recognised and correlates with neurological disability. The reasons leading to axonal and neuronal injury are diverse and possibly change from an inflammatory mediated mechanism to a neurodegenerative mechanism over the course of the disease. Acute axonal injury is associated with inflammation in the CNS and thus immunomodulatory treatments may also protect neurons from further damage. However, more effective immune treatments also bear the risk for severe side effects. Thus, neuroprotection will become more important to be combined with safe immunomodulation. Although several targets for neuroprotection have been identified experimentally, the translation into clinical treatments proves very difficult. Only few and small trials have investigated substances that may be neuroprotective, however, none had proven to have a substantial effect in MS patients. Clinical trials of remyelination, considered as a natural way of neuroprotection, were likewise not able to achieve clinical benefit. Thus, the development of a neuroprtective treatment in MS will be a major challenge in the decades to come.