How the immune response matures from recognizing a single or a few structures of the antigen to many is an obviously important process. Models of B-cell epitope spreading have been developed in a variety of systems. For example, immunization of animals with PPPGMRPP, one of the earliest B-cell epitopes in the anti-Sm response found in human lupus, leads to antispliceosomal autoimmunity and features of lupus. The humoral immune response spreads from PPPGMRPP to other structures of the spliceosome in an apparently reproducible sequence. B-cell epitope spreading has provided the experimental basis from which a relationship between lupus and Epstein-Barr virus was suspected. An understanding of B-cell epitope spreading is likely to lead to important principles in basic immunology and to answers to human disease problems.