Animal models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) are inflammatory demyelinating diseases which comprise a heterogeneous group of disorders that affect the peripheral and central nervous systems. EAE presents close similarities with multiple sclerosis (MS), a chronic inflammatory disease affecting central nervous system (CNS) white matter. Many studies have shown EAE to be a particularly useful animal model for the understanding of both the mechanisms of immune-mediated CNS pathology and the progressive clinical course of multiple sclerosis. Previous data has underlined the importance of CD4+ T cell involvement in mediating the autoimmune processes associated with the destruction of myelin and the role of the T helper 1 (Th1) pattern of cytokine secretion. However, EAE studies have also demonstrated that other cells involved in innate and/or adaptive immune responses may also play a critical role in the early and progressive events of the immune reaction leading to inflammation and CNS damage. In this review, we present such new data and discuss their potent implication for future new therapeutical approaches.