Intramolecular and intermolecular epitope spreading, the development of immune cells with new reactivities different from the original immunodominant response, plays an important role in the relapses and progression of EAE and has been implicated in the progression of MS. This chapter describes the process of epitope spreading in EAE, its impact on the development on tolerance, and the induction of peptide-specific tolerance and other immune intervention modalities that can prevent epitope spreading and its consequences.