We have made the following observations regarding self-recognition during the development and progression of murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS): 1) chronic progression of EAE is accompanied by a sequential, predictable cascade of neo-autoreactivity, commonly referred to as epitope spreading, presumably caused by endogenous self-priming during autoimmune-mediated tissue damage; 2) there is an invariant relationship between the progression of EAE and the emergence of epitope spreading; 3) progression of EAE can be inhibited by the induction of antigen-specific tolerance to spreading determinants after onset of initial neurologic symptoms; 4) CD4+ Th 1 cells responding to spreading determinants are autonomously encephalitogenic; 5) epitope spreading occurs during the development of MS and in some cases involves HLA-DP class II-restricted self-recognition; and 6) progression of both EAE and MS is accompanied by the decline of primary T-cell autoreactivity associated with disease onset and by the concurrent emergence of the epitope spreading cascade. Our studies directly challenge the traditional view that EAE and MS are initiated and maintained by autoreactivity directed against a single predominant myelin protein or determinant. Our results indicate that progression of EAE and MS involves a shifting of T-cell autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the inflammatory self-recognition process during disease progression.