To determine whether an immunological or pharmaceutical product has potential for therapy in treating multiple sclerosis (MS), detailed animal models are required. To date many animal models for human MS have been described in mice, rats, rabbits, guinea pigs, marmosets, and rhesus monkeys. The most comprehensive studies have involved murine experimental allergic (or autoimmune) encephalomyelitis (EAE), Semliki Forest virus (SFV), mouse hepatitis virus (MHV), and Theiler's murine encephalomyelitis virus (TMEV). Here, we describe in detail multispecies animal models of human MS, namely EAE, SFV, MHV, and TMEV, in addition to chemically induced demyelination. The validity and applicability of each of these models are critically evaluated. 2008 Humana Press Inc.