Until recently, the search for the ‘culprit’ autoantigen towards which deleterious autoimmunity is directed in multiple sclerosis (MS) centered mostly on myelin basic protein (MBP) and proteolipid (PLP), the two most abundant protein components of central nervous system (CNS) myelin, the target tissue for the autoimmune attack in MS. Although such research has yielded important data, furthering our understanding of the disease and opening avenues for possible immune-specific therapeutic approaches, attempts to unequivocally associate MS with MBP or PLP as primary target antigens in the disease have not been successful. This has led in recent years to a new perspective in MS research, whereby different CNS antigens are being investigated for their possible role in the initiation or progression of MS. Interesting studies in laboratory animals show that T-cells directed against certain non-myelin-specific CNS antigens are able to cause inflammation of the CNS, albeit without expression of clinical disease. However, reactivity to these antigens by MS T-cells has not been demonstrated. Conversely, reactivity by MS T-cells to non-myelin-specific antigens such as heat shock proteins, could be observed, but the pathogenic potential of such reactivity has not been corroborated with the encephalitogenicity of the antigen. More relevant to MS pathogenesis may be, as we outlined in this review, the autoimmune reactivity directed against minor myelin proteins, in particular the CNS-specific myelin oligodendrocyte glycoprotein (MOG). Here, we review the current knowledge gathered on T-cell reactivity to possible target antigens in MS in the context of their encephalitogenic potential, and underline the facets which make MOG a highly relevant contender as primary target antigen in MS, albeit not necessarily the only one.