Persistent virus infections create specific problems for their hosts. Although the dynamics of immune responses after acute infection are well studied and very consistent, especially in mouse models, the patterns of responses noted during persistent infection are more complex and differ depending on the infection. In particular, CD8(+) T cell responses differ widely in quantity and quality. In this review we examine these diverse responses and ask how they may arise; in particular, we discuss the function of antigen re-encounter and the CD4(+) T cell responses to and the escape strategies of specific viruses. We focus on studies of four main human pathogens, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus and hepatitis C virus, and their animal models.