Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that is heterogeneous in its clinical manifestation and progression, as well as in its pathological mechanisms. Animal models, in particular the various forms of experimental autoimmune encephalomyelitis, have been highly valuable for studying both disease pathology and drug development. Novel technologies, such as advanced imaging systems, as well as systematic research of CNS biopsies and postmortem samples from MS patients, have brought major progress in disease understanding. Consequently, in addition to the sclerotic demyelinated plaques in the white matter, changes in normal-appearing white matter tissue ('pre-plaque') and gray matter pathology are currently regarded as central disease components. This review aims to provide current insights on several central aspects in MS research. In particular, the interplay between inflammation and neurodegeneration mediating the disease, and therapeutic strategies attempting to induce immunomodulation and neuroprotective repair processes, are discussed.