Studies aimed to elucidate the pathogenesis of the disease and to find new therapeutic options for multiple sclerosis (MS) patients heavily rely on experimental autoimmune encephalomyelitis (EAE) as a suitable experimental model. This strategy has been highly successful for the inflammatory component of the disease, but had so far little success in the development of neuroprotective therapies, which are also effective in the progressive stage of the disease. Here we discuss opportunities and limitations of EAE models for MS research and provide an overview on the complex mechanisms leading to demyelination and neurodegeneration in this disease. We suggest that the underlying mechanisms involve adaptive and innate immunity. However, mitochondrial injury, resulting in energy failure, is a key element of neurodegeneration in MS and is apparently driven by radical production in activated microglia.