Chronic progression of relapsing experimental autoimmune encephalomyelitis (R-EAE), a mouse model of multiple sclerosis (MS), is dependent on the activation of T cells to endogenousmyelin epitopes, that is, epitope spreading. This review focuses on the cellular and molecular mechanisms underlying the process of epitope spreading. Surprisingly, activation of naïve T cells to endogenous myelin epitopes in SJL mice undergoing R-EAE occurs directly in the central nervous system (CNS), a site generally perceived to be immunologically privileged. Determination of the antigen presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with established REAE shows that peripherally derived CD11b+CD11c +CD45hi myeloid dendritic cells (mDCs) most efficiently present endogenous myelin antigens to activate both preactivated effector myelin-specific T cells and naïve T cells. The mDCs, which drive epitope spreading, preferentially polarize pathogenic Th17 responses correlating with their enhanced expression of TGF-β1, IL-6, and IL-23. Both B220 +CD11c+ plasmacytoid (pDCs) and CD8α +CD11c+ (CD8 DCs) were superior to CD11b +CD11c-CD45hi macrophages, but less efficient than mDCs at presenting endogenous peptide to induce Th17 cells. In contrast, CNS-resident CD11b+CD11c-CD45low microglia purified from the inflamed CNS were found to be largely incapable of activating either naïve or effector T cells.