Multiple sclerosis (MS) is a chronic neurodegenerative disease that causes central nervous system (CNS) inflammation and demyelination, affecting approximately two million people worldwide. In humans, different subtypes of the disease have been noted, characterized by distinct clinical courses and different histopathological manifestations. These disease variants likely result from the targeting of different neuroantigens in the CNS and possibly from the involvement of different effector arms of the immune system such as CD4(+) and CD8(+) T cells as well as autoantibodies. Mechanistic studies addressing the pathomechanisms of MS involve experimental autoimmune encephalomyelitis (EAE) in which immunization with neuroantigens is used to elicit the disease. Mechanism-oriented studies of EAE rely mostly on gene-modified mice on the C57BL/6 (B6) background. Here, we discuss how a systematic immuno- and histopathological comparison of the presently available EAE models on the B6 background, i.e. myelin basic protein-proteolipid protein (MBP-PLP) fusion protein (MP4)-, myelin oligodendrocyte glycoprotein (MOG) peptide 35-55- and PLP peptide 178-191-induced EAE, can facilitate our understanding of the complexity of MS. We point out how the development of further models on this basis can help cover the plethora of disease manifestations seen in MS.