Multiple sclerosis is an immune-mediated disorder of the central nervous system. Major pathological characteristics include the loss of oligodendrocytes, demyelination and neuroaxonal depletion in association with inflammation. The complex pathophysiology of tissue loss is only partially understood. Here we discuss a variety of mitochondrion-driven mechanisms involved in immune regulation, oligodendrocyte depletion and neurodegeneration. The recognition of a mitochondrial link between inflammation and neurodegeneration underscores the importance of an early aggressive intervention for halting inflammation and preventing neurodegeneration, and identifies the mitochondrion as a potential target in neuroprotection.