Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the CNS, and imposes major burdens on young lives. Great progress has been made in understanding and moderating the acute inflammatory components of MS, but the pathophysiological mechanisms of the concomitant neurodegeneration--which causes irreversible disability--are still not understood. Chronic inflammatory processes that continuously disturb neuroaxonal homeostasis drive neurodegeneration, so the clinical outcome probably depends on the balance of stressor load (inflammation) and any remaining capacity for neuronal self-protection. Hence, suitable drugs that promote the latter state are sorely needed. With the aim of identifying potential novel therapeutic targets in MS, we review research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction. We focus on mechanisms inherent to neurons and their axons, which are separable from those acting on inflammatory responses and might, therefore, represent bona fide neuroprotective drug targets with the capability to halt MS progression.