Adaptation of persistent infection within the cells of the immune system is a unique characteristic of gamma herpes viruses. A classic example of this is Epstein-Barr virus (EBV), which may have co-evolved with Homo sapiens over millions of years, thus achieving a balance between viral persistence and immune control. In this review, we present an overview of virus and the host immune system interactions that regulate the life-long host-virus relationship in healthy virus carriers and EBV-associated diseases. Extensive analysis of cytotoxic T lymphocyte-mediated immune responses in healthy virus carriers has revealed unique mechanisms used by EBV to maintain a benign persistent state in vivo. On the other hand, this relationship in EBV-associated diseases favors the escape of the virus from the hostile effects of the immune response. This escape is achieved by either down-regulating the expression of highly immunogenic antigens of the virus or by direct modulation of the host cytotoxic T lymphocyte response by virus-encoded proteins.